Oriented implants containing poly(butylene succinate) and copolymer, and methods of use thereof

ABSTRACT

Resorbable implants comprising poly(butylene succinate) and copolymers thereof have been developed. The implants implants are preferably sterilized, and contain less than 20 endotoxin units per device as determined by the limulus amebocyte lysate (LAL) assay, and are particularly suitable for use in procedures where prolonged strength retention is necessary, and can include one or more bioactive agents. The implants may be made from fibers and meshes of poly(butylene succinate) and copolymers thereof, or by 3d printing, and the fibers may be oriented. Coverings and receptacles made from forms of poly(butylene succinate) and copolymers thereof have also been developed for use with cardiac rhythm management devices and other implantable devices. These coverings and receptacles may be used to hold, or partially/fully cover, devices such as pacemakers and neurostimulators. The coverings and receptacles are made from meshes, webs, lattices, non-wovens, films, fibers, and foams, and contain antibiotics such as rifampin and minocycline.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ApplicationNo. 62/636,930, filed Mar. 1, 2018 and U.S. Application No. 62/733,384,filed on Sep. 19, 2018, which is hereby incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

The present invention generally relates to oriented implants made fromresorbable polymeric compositions and methods of use thereof. Thedevices contain poly(butylene succinate) and copolymers thereof.

BACKGROUND OF THE INVENTION

Multifilament products made from resorbable polymers, such as copolymersof glycolide and lactide, and monofilament products made from resorbablepolymers, such as polydioxanone (PDO), are well known in the prior art,and widely used in wound closure and general surgery. However, theseproducts undergo rapid loss of strength retention in vivo, which limitstheir application primarily to fast healing repairs, and repairs whereprolonged strength retention is not necessary. For example, while asurgeon may use a resorbable multifilament suture to approximate softtissue that is not under significant tension, a surgeon will generallynot use a resorbable suture when loads on the suture can be very highand remain high for a prolonged period, such as in rotator cuff repairs.Instead, surgeons will typically use permanent sutures for rotator cuffrepairs even though it would be desirable to use a suture that iscompletely resorbed once healing is complete. Similarly, a surgeon mayuse a resorbable monofilament suture or mesh to approximate soft tissuethat is not under significant tension, but will generally not use aresorbable monofilament suture or mesh when loads on the device can bevery high and remain high for a prolonged period, such as in herniarepair. Instead, surgeons will typically use permanent (polypropylene)meshes for hernia repairs even though it would be desirable to usedevices that completely resorb after healing is complete.

Recently, an aliphatic polyester, poly(butylene succinate) (PBS) hasbeen commercialized for use in industrial applications such as papercoatings, packaging, and mulch films (U.S. Pat. No. 7,317,069 toAoshima, U.S. Pat. No. 8,680,229 to Maeda, U.S. Pat. No. 8,747,974 toNakano, W02014173055A1 to Xu, and US Patent Application 20100249332 toFerguson.). The industrial polymer is produced through condensationpolymerization from readily available starting materials, succinic acidand 1,4-butanediol. Xu and Guo, Biotechnol. J. 5:1149-1163 (2010) havereviewed the industrialization of the PBS polymer, Li et al. haveevaluated poly(butylene succinate) in vitro (Li et al. Macromol. Biosci.5:433-440 (2005)), Vandesteene et al. Chin. J. Polym. Sci.,34(7):873-888 (2016) have studied the structure-property relationshipsof the polymer. Kun et al. ASAIO Journal, 58:262-267 (2012) have studiedthe biocompatibility of blends of PBS with polylactic acid, and Gigli etal. Eur. Polym. J., 75:431-460 (2016) have reviewed the polymer's invitro biocompatibility. However, no FDA-approved implants containingpoly(butylene succinate) or copolymers thereof have been successfullydeveloped.

One reason that progress in developing implants made from PBS andcopolymers thereof has been prevented is that the mechanical propertiesof the polymers were unsatisfactory, particularly when compared toalternative medical grade polymers. Low molecular weights of PBS andcopolymers thereof were mainly responsible for the poor mechanicalproperties. In order to increase molecular weight, new methods ofpolymer synthesis have more recently been successfully developed, andindustrial products made from PBS and copolymers thereof have now beenintroduced. These advances in improving molecular weight relied upon theuse of isocyanate chemistry to increase the molecular weight of PBS, andprovide polymers with good mechanical properties (U.S. Pat. No.5,349,028). Unfortunately, this approach is not a good option for thedevelopment of biocompatible degradable implants due to the toxicityassociated with isocyanate chemistry.

In the practice of surgery there currently exists a need for resorbablefibers with high tensile strength and prolonged strength retention.These fibers, including multifilament yarns and monofilament fibers,would allow the surgeon to use resorbable devices instead of permanentdevices when high strength is initially required, or when prolongedstrength retention is necessary. For example, monofilament resorbablefibers with high strength and prolonged strength retention could be usedto make monofilament surgical meshes suitable for hernia repair, breastreconstruction and mastopexy, treatment of stress urinary incontinence,and pelvic floor reconstruction. And multifilament yarns with hightenacity and prolonged strength retention could be used, for example, inthe repair of the rotator cuff and other ligaments and tendons, as wellas for hernia repair or breast lift procedures. Other processingtechniques, such as 3D printing, including fused filament fabrication,could also be used to make implants with prolonged strength retention,including lattices and other porous constructs, suitable for use in, forexample, hernia repair, breast reconstruction and mastopexy, treatmentof stress urinary incontinence, and pelvic floor reconstruction.

There is thus a need to develop resorbable implants with prolongedstrength retention and preferably high initial tensile strength thatalso have good biocompatibility, can be produced economically, anddegrade to non-toxic degradation products.

It is an object of the present invention to provide biocompatibleimplants of poly(butylene succinate) and copolymers thereof withprolonged strength retention.

It is a further object of the present invention to provide implants ofpoly(butylene succinate) and copolymers thereof that are made fromoriented fibers, including monofilament and multifilament fibers.

It is yet a further object of the present invention to provide implantsof poly(butylene succinate) and copolymers thereof that are made by 3Dprinting.

It is another object of the present invention to provide processes toproduce oriented implants and 3D printed implants of poly(butylenesuccinate) and copolymers thereof.

It is still another object of the invention to provide methods forimplantation of implants made from poly(butylene succinate) andcopolymers thereof.

SUMMARY OF THE INVENTION

Resorbable biocompatible implants comprising poly(butylene succinate)and copolymers thereof have been developed. These implants are madeusing poly(butylene succinate), copolymers, or blends thereof, and areproduced so that the implants are biocompatible, contain less than 20endotoxin units per device as determined by the limulus amebocyte lysate(LAL) assay, and are sterile. The poly(butylene succinate) polymercomprises succinic acid and 1,4-butanediol, two compounds that areconverted by hydrolysis to natural metabolites in vivo, and whichdegrade by known metabolic/catabolic pathways to carbon dioxide andwater without the formation of toxic metabolites. The poly(butylenesuccinate) and copolymers thereof are also made without the use of crosslinking agents that can result in toxic metabolites being released fromthe implants as the polymers degrade. The implants are particularlysuitable for use in procedures where prolonged strength retention isnecessary, such as hernia repair, breast reconstruction andaugmentation, mastopexy, orthopedic repairs, wound management, pelvicfloor reconstruction, treatment of stress urinary incontinence,stenting, heart valve surgeries, dental procedures and other plasticsurgeries. The preparation of the implants avoids the use of productiontechnologies that produce endotoxin, or require the use of antibiotics.Preferably, the implants are made from polymeric compositions ofpoly(butylene succinate) and copolymers thereof, wherein the meltingtemperatures of the compositions are between 105° and 120° C., and thusthe implants are stable during transportation in hot climates as well asin storage. The polymeric compositions used to prepare the implantspreferably exclude the use of poly(butylene succinate) and copolymersthereof that have been prepared with the use of isocyanates. In apreferred embodiment, the implants comprise polymeric compositionscomprising 1,4-butanediol and succinic acid units copolymerized with oneor more hydroxycarboxylic acid units, even more preferably wherein thehydroxycarboxylic acid units are malic acid, citric acid, or tartaricacid. In a particularly preferred embodiment, the implants comprisesuccinic acid-1,4-butanediol-malic acid copolyester. In anotherembodiment, the implants comprise polymeric compositions comprising1,4-butanediol and succinic acid units copolymerized with maleic acid,fumaric acid, or combinations thereof. These polymeric compositions mayfurther comprise other monomers, including malic acid, citric acid ortartaric acid.

In an embodiment, the implants are made from fibers and meshescomprising poly(butylene succinate) and copolymers thereof. In apreferred embodiment, the fibers are oriented. It has been discoveredthat the oriented fibers do not curl when uneven forces are applied totheir surfaces during implantation. For example, these fibers do notcurl, or form pig tail structures, when used as sutures and tension isapplied unevenly to the suture's surfaces. Pig tailing of suture fibersis undesirable because it makes the handling of surgical sutures verydifficult during implantation. It has also been discovered that orientedfibers of poly(butylene succinate) and copolymers thereof can beprepared that are not pitted during degradation after implantation invivo. This fiber property provides a predictable degradation profile invivo, and is particularly important for the performance of smalldiameter fibers and multifilament fibers. Pitting of the surface of asmall diameter fiber, or uneven erosion of the fiber surface, can resultin the premature loss of strength retention of the fiber leading toearly failure of the fiber in vivo. Premature loss of strength retentionresults from the effective cross-section of the fiber being decreased bypitting. The absence of pitting of the fibers is particularly importantin all fiber-based implants, and especially important in implants whereprolonged strength retention is desirable like sutures, surgical meshes,hernia meshes, breast reconstruction meshes, mastopexy meshes, andslings. Pitting can be visualized using SEM as indents, micropores orhollowing of the surface of the fiber.

In one embodiment, oriented monofilament and multifilament fibers ofpoly(butylene succinate) and copolymers have been developed with veryhigh tensile strengths, but that still degrade in vivo over time. It hasbeen discovered that these fibers can be prepared using multi-stageorientation in combination with heated conductive liquid chambers. Thehigh tensile strengths of these fibers make them suitable for use inresorbable implant applications requiring high tensile strength andprolonged strength retention. Such applications include hernia repair,breast reconstruction, treatment of urinary incontinence with slings,suturing, mesh suturing, and ligament and tendon repair. In anotherembodiment, it has been discovered that this new method of fiberformation can also be used to prepare oriented monofilament andmultifilament fibers of poly(butylene succinate) and copolymers that arerelatively stiff with Young's Modulus values between 2 and 3 GPa. Thehigh stiffness of these fibers is particularly advantageous in thepreparation, handling, and performance of resorbable implantable suturesand surgical meshes. It has also been found that the poly(butylenesuccinate) and copolymer compositions can be used to prepare orthopedicimplants with sufficient stiffness and torsional strengths to make themuseful in resorbable implants such as interference screws and sutureanchors. It has also been discovered that surgical meshes can beprepared from poly(butylene succinate) and copolymers thereof that aredimensionally stable when implanted in vivo, and do not shrink for atleast 4 weeks, or at least 12 weeks, following implantation, i.e., thewidth and length of the mesh do not decrease in size substantially, orsignificantly. In Table 8 shows that the relative area of the mesh doesnot shrink. The width and length remain relatively constant. Whereasdata for the GalaFLEX mesh is given in Table 9, and the area of the meshand dimensions decrease. Accordingly, in this embodiment, the area ofthe mesh decreases by less than 6, for example, less than 5%, less than4%, less than 2% and less than 1% by 12 weeks compared to its initialarea, and the area of the mesh decreases by less than 4%, preferably,less than 2% and even more preferably between 0% and 1% at 4 weeks postimplantation, compared to its initial area.

The surgical meshes are prepared from oriented fibers of poly(butylenesuccinate) and copolymers thereof. The improved meshes preventadditional tension being placed on tissues at the implant site, andmaintain the original area of reinforcement or repair. Furthermore, ithas also been discovered that the meshes do not curl along their edgesafter implantation, and continue to contour to the patient's anatomy.Curling of implantable mesh along its edges is undesirable because itcan expose neighboring tissue to mesh edges and result in tissue damage.

In a further embodiment, the implants are made by 3D printingcompositions comprising poly(butylene succinate) and copolymers thereof.In a particularly preferred embodiment, the implants made by 3D printinghave porous structures, and even more preferably lattice structures. Ithas been discovered that certain compositions of poly(butylenesuccinate) and copolymers thereof can be 3D printed to produce implantswhere surprisingly the printed polymers have a higher weight averagemolecular weight than the compositions from which they are derived.

In another embodiment, the implants contain one or more antimicrobialagents to prevent colonization of the implants, and reduce or preventthe occurrence of infection following implantation in a patient.Coverings and receptacles made from forms of poly(butylene succinate)and copolymers thereof have also been developed for use with cardiacrhythm management devices and other implantable devices. These coveringsand receptacles may be used to hold, or partially or fully cover,devices such as pacemakers, breast implants, and neurostimulators. In apreferred embodiment, the coverings and receptacles are made frommeshes, non-wovens, films, fibers, foams, 3D printed objects, andcontain antibiotics such as rifampin and minocycline. The implantscomprising poly(butylene succinate) and copolymers thereof can besterilized by irradiation, but are more preferably sterilized byethylene oxide gas or cold ethylene oxide gas.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an image showing a 3D printed mesh produced by melt extrusiondeposition (MED) of succinic acid-1,4-butanediol-malic acid copolyester.

FIG. 2 is an image of a paraffin-embedded tissue slide showing thehistology of a PBS mesh after subcutaneous implantation in a rabbit fora 4-week period using an H&E stain at a magnification of 20×.

FIG. 3 is an image of a paraffin-embedded tissue slide, showing thehistology of a PBS mesh after subcutaneous implantation in a rabbit fora 4-week period using an H&E stain at a magnification of 200×.

FIG. 4 is a SEM image of an oriented PBS monofilament suture fiber priorto implantation at a 400× magnification showing a smooth surface.

FIG. 5 is a SEM image of an oriented PBS monofilament suture fiber afterimplantation at a rabbit subcutaneous site for 4 weeks. The image showsa smooth surface with no surface pitting or localized erosion of thesurface at a 400× magnification.

DETAILED DESCRIPTION OF THE INVENTION

Methods have been developed to prepare resorbable implants withprolonged strength retention that contain poly(butylene succinate) orcopolymer thereof. These implants preferably have high initial strength,and contain less than 20 endotoxin units per device as determined by thelimulus amebocyte lysate (LAL) assay. After implantation, the implantsdegrade slowly providing sufficient time for healing before the strengthof the implant is lost. In certain embodiments, the implants are in theform of scaffolds which allow tissue ingrowth to occur over a prolongedperiod of time on account of the prolonged strength retention. Theimplants may contain one or more antimicrobial agents to preventcolonization of the implants, and reduce or prevent the occurrence ofinfection following implantation in a patient. After implantation, theimplants are designed to release the antimicrobial agents. The implantsmay also be coated on one or more surfaces to prevent adhesions formingto the coated surfaces. In one embodiment, the implants may be deliveredminimally invasively, and the implants may also be three-dimensionalwith or without the ability to resume their original shapes after beingdeformed for delivery. The implants are particularly suitable for use inprocedures where prolonged strength retention is required, such ashernia repair, including abdominal, ventral, incisional, umbilical,inguinal, femoral, hiatal and paraesophageal hernia, breastreconstruction and augmentation, mastopexy, orthopedic repairs includingligament and tendon repair, wound management, suturing, pelvic floorreconstruction, treatment of stress urinary incontinence, stenting,heart valve surgeries, dental procedures and other plastic surgeries. Inone preferred embodiment, methods have been developed to produceimplants with highly oriented fibers and meshes of poly(butylenesuccinate) and copolymers thereof. Maintenance of the high degree oforientation of these fibers and meshes is essential to their physicalfunction in vivo. The high degree of orientation of the fibers andmeshes allows these devices to retain strength in the body for prolongedperiods (“prolonged strength retention”), and therefore provide criticalsupport to tissues during reconstruction and repair procedures. Iforientation is lost during preparation of the implants containing thesefibers and meshes, the resulting products will have lower strength andstrength retention, and be unable to provide the necessary reinforcementand configuration required for healing. For example, spray coating ordip coating of oriented poly(butylene succinate) fibers using manysolvents results in loss of fiber orientation and loss of strengthretention. Methods have been developed that allow fibers and meshes ofpoly(butylene succinate) and copolymers thereof to be prepared withoutsubstantial loss of orientation of the fibers, and therefore withoutsubstantial loss of strength and strength retention. Optionally, theseimplants may also incorporate other bioactive agents, such asantibiotics, antimicrobials, and anti-adhesion agents.

In another preferred embodiment, methods have been developed to produceimplants of poly(butylene succinate) and copolymers by 3D printing,including free deposition modeling, including fused filamentfabrication, fused pellet deposition, and melt extrusion deposition,selective laser melting, and solution printing. A particularly preferred3D printing method is fused filament fabrication. In a preferredembodiment, the implants comprising poly(butylene succinate) andcopolymers produced by 3D printing are porous, and in a particularlypreferred embodiment the implants may be lattices, including meshescontaining struts or fibers.

Methods have also been developed to prepare resorbable enclosures,pouches, holders, covers, meshes, non-wovens, films, clamshells,casings, and other receptacles made from poly(butylene succinate) andcopolymers thereof that partially or fully encase, surround or holdimplantable medical devices, and optionally wherein the poly(butylenesuccinate) and copolymers thereof contain and release one or moreantimicrobial agents to prevent colonization of the implants and/orreduce or prevent infection. Implantable medical devices that can bepartially or fully encased include cardiac rhythm management (CRM)devices (including pacemakers, defibrillators, and generators),implantable access systems, neurostimulators, ventricular accessdevices, infusion pumps, devices for delivery of medication andhydration solutions, intrathecal delivery systems, pain pumps, breastimplants, and other devices to provide drugs or electrical stimulationto a body part.

In one embodiment, the methods disclosed herein are based upon thediscovery that oriented implants and 3D printed implants ofpoly(butylene succinate) and copolymers thereof retain their strengthlonger than copolymers of glycolide and lactide, and monofilamentproducts made from polydioxanone (PDO). The oriented and 3D printedimplants of poly(butylene succinate) and copolymers thereof can also beprepared with high initial strength.

Methods have also been developed to prepare resorbable implantscomprising poly(butylene succinate) and copolymers thereof that may beused for soft and hard tissue repair, regeneration, and replacement.These implants include, but not limited to: suture, barbed suture,braided suture, monofilament suture, hybrid suture of monofilament andmultifilament fibers, braids, ligatures, knitted or woven meshes,knitted tubes, catheters, monofilament meshes, multifilament meshes,patches, wound healing device, bandage, wound dressing, burn dressing,ulcer dressing, skin substitute, hemostat, tracheal reconstructiondevice, organ salvage device, dural substitute, dural patch, nerveguide, nerve regeneration or repair device, hernia repair device, herniamesh, hernia plug, device for temporary wound or tissue support, tissueengineering scaffold, guided tissue repair/regeneration device,anti-adhesion membrane, adhesion barrier, tissue separation membrane,retention membrane, sling, device for pelvic floor reconstruction,urethral suspension device, device for treatment of urinaryincontinence, device for treatment of vesicoureteral reflux, bladderrepair device, sphincter muscle repair device, injectable particles,injectable microspheres, bulking or filling device, bone marrowscaffold, clip, clamp, screw, pin, nail, medullary cavity nail, boneplate, interference screw, tack, fastener, rivet, staple, fixationdevice for an implant, bone graft substitute, bone void filler, sutureanchor, bone anchor, ligament repair device, ligament augmentationdevice, ligament graft, anterior cruciate ligament repair device, tendonrepair device, tendon graft, tendon augmentation device, rotator cuffrepair device, meniscus repair device, meniscus regeneration device,articular cartilage repair device, osteochondral repair device, spinalfusion device, device for treatment of osteoarthritis, viscosupplement,stent, including coronary, cardiovascular, peripheral, ureteric,urethral, urology, gastroenterology, nasal, ocular, or neurology stentsand stent coatings, stent graft, cardiovascular patch, catheter balloon,vascular closure device, intracardiac septal defect repair device,including but not limited to atrial septal defect repair devices and PFO(patent foramen ovale) closure devices, left atrial appendage (LAA)closure device, pericardial patch, vein valve, heart valve, vasculargraft, myocardial regeneration device, periodontal mesh, guided tissueregeneration membrane for periodontal tissue, ocular cell implant,imaging device, cochlear implant, embolization device, anastomosisdevice, cell seeded device, cell encapsulation device, controlledrelease device, drug delivery device, plastic surgery device, breastlift device, mastopexy device, breast reconstruction device, breastaugmentation device, breast reduction device, devices for breastreconstruction following mastectomy with or without breast implants,facial reconstructive device, forehead lift device, brow lift device,eyelid lift device, face lift device, rhytidectomy device, thread liftdevice to lift and support sagging areas of the face, brow and neck,rhinoplasty device, device for malar augmentation, otoplasty device,neck lift device, mentoplasty device, cosmetic repair device, and devicefor facial scar revision. In a particularly preferred embodiment, theseimplants comprise polymeric compositions comprising 1,4-butanediol andsuccinic acid units copolymerized with one or more hydroxycarboxylicacid units, even more preferably wherein the hydroxycarboxylic acidunits are malic acid, citric acid, or tartaric acid. In a particularlypreferred embodiment, these implants comprise succinicacid-1,4-butanediol-malic acid copolyester. In another embodiment, theimplants comprise polymeric compositions comprising 1,4-butanediol andsuccinic acid units copolymerized with maleic acid, fumaric acid, orcombinations thereof. These polymeric compositions may further compriseother monomers, including malic acid, citric acid or tartaric acid.

I. Definitions

“Bioactive agent” is used herein to refer to therapeutic, prophylactic,and/or diagnostic agents. It includes without limitation physiologicallyor pharmacologically active substances that act locally or systemicallyin the body. A biologically active agent is a substance used for, forexample, the treatment, prevention, diagnosis, cure, or mitigation ofdisease or disorder, a substance that affects the structure or functionof the body, or pro-drugs, which become biologically active or moreactive after they have been placed in a predetermined physiologicalenvironment. Bioactive agents include biologically, physiologically, orpharmacologically active substances that act locally or systemically inthe human or animal body. Examples can include, but are not limited to,small-molecule drugs, peptides, proteins, antibodies, antimicrobials,antibiotics, antiparasitic agents, sugars, polysaccharides, nucleotides,oligonucleotides, hyaluronic acid and derivatives thereof, aptamers,siRNA, nucleic acids, and combinations thereof. “Bioactive agent”includes a single such agent and is also intended to include aplurality.

“Biocompatible” as generally used herein means the biological responseto the material or device being appropriate for the device's intendedapplication in vivo. Any metabolites or degradation products of thesematerials should also be biocompatible.

“Blend” as generally used herein means a physical combination ofdifferent polymers, as opposed to a copolymer comprised of two or moredifferent monomers.

“Burst strength” as used herein unless otherwise stated is determined bytest method based on ASTM D6797-02 “Standard test method for burstingstrength of fabrics constant rate of extension (CRE) ball burst test,”using a MTS Q-Test Elite universal testing machine or similar device.However, the testing fixture uses a ⅜ inch diameter ball and the openingis ½ inch diameter.

“Copolymers of poly(butylene succinate)” as generally used herein meansany polymer of succinic acid and butylene monomers incorporating one ormore additional monomers. Examples of copolymers of poly(butylenesuccinate) include poly(butylene succinate-co-adipate), poly(butylenesuccinate-co-terephthalate), poly(butylene succinate-co-ethylenesuccinate), and poly(butylene succinate-co-propylene succinate).Poly(butylene succinate-co-adipate), for example, may be made bycondensation polymerization from succinic acid, adipic acid and1,4-butanediol. Copolymers of poly(butylene succinate) include polymerscomprising (i) succinic acid and 1,4-butanediol units, and (ii) one ormore of the following additional units, such as: chain extenders,cross-linking agents, and branching agents. Examples of these copolymersinclude: succinic acid-1,4-butanediol-malic acid copolyester, succinicacid-1,4-butanediol-citric acid copolyester, succinicacid-1,4-butanediol-tartaric acid copolyester, succinicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or a combination thereof, succinic acid-adipicacid-1,4-butanediol-malic acid copolyester, succinic acid-adipicacid-1,4-butanediol-citric acid copolyester, succinic acid-adipicacid-1,4-butanediol-tartaric acid copolyester, or succinic acid-adipicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or combinations thereof. Copolymers ofpoly(butylene succinate) also include polymers comprising succinic acidand 1,4-butanediol units and one or more hydroxycarboxylic acid unit.The copolymers may also comprise maleic or fumaric acid units, orcombinations thereof.

“Diameter” as generally used herein is determined according to the USPharmacopeia (USP) standard for diameter of surgical sutures (USP 861).

“Elongation” or “extensibility” of a material means the amount ofincrease in length resulting from, as an example, the tension to break aspecimen. It is expressed usually as a percentage of the originallength. (Rosato's Plastics Encyclopedia and Dictionary, Oxford Univ.Press, 1993).

“Endotoxin content” as used herein refers to the amount of endotoxinpresent in a sample, and is determined by the limulus amebocyte lysate(LAL) assay.

“Mesh suture” as used herein means a device including a needle and amesh component that can be used to re-appose soft tissue. The meshsuture is designed to be threaded through soft tissue, and the meshcomponent anchored under tension to re-appose soft tissue. The meshcomponent helps to prevent the suture from cutting through the tissues(suture pullout or cheese-wiring), and increases the strength of therepair, when compared to conventional monofilament and multifilamentsutures.

“Molecular weight” as used herein, unless otherwise specified, refers tothe weight average molecular weight (Mw), not number average molecularweight (Mn), and is measured by gel permeation chromatography (GPC)relative to polystyrene standards.

“Orientation ratio” as used herein is the ratio of the output speed tothe input speed of two godets (or rollers) used to orient themultifilament yarn or monofilament fiber. For example, the orientationratio would be 3 if the output speed of the multifilament yarn ormonofilament fiber is 6 meters per minute, and the input speed of themultifilament yarn or monofilament fiber is 2 meters per minute.

“Phosphate buffered saline” as used herein is prepared by diluting a 10×Phosphate Buffered Saline, Ultra Pure Grade (Product # J373-4L, fromVWR) to 1× with deionized water and adding 0.05 wt % sodium azide (NaN3,Product # 14314 from Alfa Aesar) as a biocide. The resulting 1× buffersolution contains 137 mM NaCl, 2.7 mM KCl, 9.8 mM phosphate and 0.05 wt% sodium azide and has pH 7.4 at 25° C. The prepared solution isfiltered through a 0.45 μm filter (VWR Product # 10040-470) prior touse.

“Poly(butylene succinate)” as generally used herein means an aliphaticpolyester containing succinic acid and 1,4-butanediol units, and may bemade by condensation polymerization from succinic acid and1,4-butanediol.

Poly(butylene succinate) may be abbreviated as “PBS”. Poly(butylenesuccinate) includes polymers of (i) succinic acid and 1,4-butanediolunits, and (ii) one or more additional monomers, including thefollowing: chain extenders, cross-linking agents, and branching agents.

“Resorbable” as generally used herein means the material is broken downin the body and eventually eliminated from the body. The terms“resorbable”, “degradable”, “erodible”, and “absorbable” are usedsomewhat interchangeably in the literature in the field, with or withoutthe prefix “bio”. Herein, these terms will be used interchangeably todescribe material broken down and gradually absorbed or eliminated bythe body within five years, whether degradation is due mainly tohydrolysis or mediated by metabolic processes.

“Strength retention” refers to the amount of time that a materialmaintains a particular mechanical property following implantation into ahuman or animal. For example, if the tensile strength of a resorbablefiber decreased by half over 3 months when implanted into an animal, thefiber's strength retention at 3 months would be 50%.

“Suture pullout strength” as used herein means the peak load (kg) atwhich an implant fails to retain a suture. It is determined using atensile testing machine by securing an implant in a horizontal holdingplate, threading a suture in a loop through the implant at a distance of1 cm from the edge of the implant, and securing the suture arms in afiber grip positioned above the implant. Testing is performed at acrosshead rate of 100 mm/min, and the peak load (kg) is recorded. Thesuture is selected so that the implant will fail before the suturefails.

“Taber Stiffness Unit” is defined as the bending moment of ⅕ of a gramapplied to a 1 ½″ (3.81 cm) wide specimen at a 5-centimeter test length,flexing it to an angle of 15°, and is measured using a Taber V-5Stiffness Tester Model 150-B or 150-E. The TABER® V-5 StiffnessTester-Model 150-B or 150-E is used to evaluate stiffness and resiliencyproperties of materials up to 10,000 Taber Stiffness Units. Thisprecision instrument provides accurate test measurement to ±1.0% forspecimens 0.004″ to 0.219″ thickness. One Taber Stiffness Unit is equalto 1 gram cm (g cm) or 0.0981 milliNewton meters (mN m). Taber StiffnessUnits can be converted to Genuine Gurley™ Stiffness Units with theequation: S_(T)=0.01419S_(G)−0.935, where S_(T) is the stiffness inTaber Stiffness Units and S_(G) is the stiffness in Gurley StiffnessUnits. To convert Taber Stiffness Units to milliNewton Meters, use theequation: X=S_(T)·0.098067, where X is the stiffness in milliNewtonMeters. When explants do not meet the size requirements for the Tabertest due to limitations in the available testing sizes for implantationin an experimental animal, the values may be used to determine changesin the relative stiffness or provide comparative values between samplesof the same size.

“Tenacity” means the strength of a yarn or a filament for its givensize, and is measured as the grams of breaking force per denier unit ofyarn or filament and expressed as grams per denier (gpd).

“Tensile modulus” is the ratio of stress to strain for a given materialwithin its proportional limit.

“Tensile strength” as used herein means the maximum stress that amaterial can withstand while being stretched or pulled before failing orbreaking.

“Yarn” as used herein means a continuous strand of textile fibers, orfilaments. The yarn may be twisted, not twisted, or substantiallyparallel strands.

II. Compositions

Methods have been developed to produce resorbable implants comprisingpoly(butylene succinate) and copolymers thereof. The resorbable implantsmay be used for soft and hard tissue repair, regeneration, andreplacement.

In one embodiment, the implants comprise fibers with prolonged strengthretention. The fibers may be monofilament or multifilament fibers, andare preferably oriented. The fibers preferably have an in vivo strengthretention of at least 70% at 4 weeks, and more preferably at least 80%or 90% strength retention at 4 weeks. The fibers preferably have an invivo strength retention of at least 50% at 12 weeks, and more preferablyat least 65% strength retention at 12 weeks. These properties make thefibers suitable for use in implants requiring prolonged strengthretention, such as hernia meshes, breast reconstruction meshes, sutures,slings for treatment of stress urinary incontinence, mesh sutures, andpelvic floor reconstruction devices. In addition to having prolongedstrength retention, these fibers preferably have one or more of thefollowing properties: (i) tensile strengths greater than 400 MPa, 500MPa, 600 MPa, 700 MPa, or 800 MPa, but less than 2,000 Pa, and morepreferably between 400 MPa and 1,200 MPa, (ii) Young's Modulus greaterthan 600 MPa, 700 MPa, 800 MPa, 900 MPa, 1 GPa, or 2 GPa, but less than3GPa, and (iii) elongation to break of 10-150%, more preferably 10-50%.

Methods have also been developed to produce implants comprising PBS orcopolymer thereof that can partially or fully encase, surround or holdimplantable medical devices, and wherein the PBS or copolymers thereofrelease one or more antimicrobial agents to prevent colonization of theimplantable medical devices and/or reduce or prevent infection in thepatient. Suitable implants comprising PBS or copolymers thereof includepouches, holders, covers, meshes, non-wovens, lattices, webs, films,clamshells, casings, and receptacles.

In another embodiment, methods are described to prepare implantscomprising PBS and copolymers thereof that are relatively stiff. In oneembodiment, the polymeric compositions of PBS and copolymers thereof canbe used to prepare orthopedic implants. These implants have sufficientstiffness and torsional strength to make them suitable for use inresorbable implants such as interference screws, suture anchors, boneanchors, clips, clamps, screws, pins, nails, medullary cavity nails,bone plates, interference screw, tacks, fasteners, rivets, staples,fixation devices for an implant, and bone void fillers.

Methods to process PBS and copolymers thereof by 3D printing intoresorbable implants are also described. The methods are particularlysuitable for making meshes, void fillers, lattices, tissue scaffolds andcomplex 3D shapes for use as implants.

A. Poly(butylene succinate) and Copolymers

The methods described herein can typically be used to produce resorbableimplants and resorbable enclosures, pouches, holders, covers, meshes,non-wovens, webs, lattices, films, clamshells, casings, and otherreceptacles from poly(butylene succinate) and copolymers thereof.Copolymers contain other diols and diacids in addition to the1,4-butanediol and succinate monomers, and may alternatively oradditionally contain branching agents, coupling agents, cross-linkingagents and chain extenders. Examples of diols and diacids that can beincluded are: 1,3-propanediol, ethylene glycol, 1,5-pentanediol,glutaric acid, adipic acid, terephthalic acid, malonic acid, and oxalicacid. The copolymers may contain one or more additional diols anddiacids in addition to 1,4-butanediol and succinic acid. Copolymersinclude, but are not limited to, poly(butylene succinate-co-adipate),poly(butylene succinate-co-terephthalate), poly(butylenesuccinate-co-butylene methylsuccinate), poly(butylenesuccinate-co-butylene dimethylsuccinate), poly(butylenesuccinate-co-ethylene succinate) and poly(butylenesuccinate-co-propylene succinate).

The resorbable implants described herein may be produced frompoly(butylene succinate) and copolymers thereof wherein the polymer orcopolymer has been produced using one or more of the following: chainextenders or coupling agents, cross-linking agents, and branchingagents. For example, poly(butylene succinate) or copolymer thereof maybe branched or cross-linked by adding one or more of the followingagents: malic acid, trimethylol propane, trimesic acid, citric acid,glycerol propoxylate, and tartaric acid. Particularly preferred agentsfor branching or cross-linking are hydroxycarboxylic acid units.Preferably the hydroxycarboxylic acid unit has two carboxyl groups andone hydroxyl group, two hydroxyl groups and one carboxyl group, threecarboxyl groups and one hydroxyl group, or two hydroxyl groups and twocarboxyl groups. In one preferred embodiment, the implants are preparedfrom poly(butylene succinate) comprising malic acid as a branching orcross-linking agent. The composition may be referred to aspoly(1,4-butylene glycol-co-succinic acid), cross-linked with malicacid, poly(butylene succinate), cross-linked with malic acid, orsuccinic acid-1,4-butanediol-malic acid copolyester. It should be notedthat the malic acid may dehydrate at high temperature, for exampleduring melt extrusion, into maleic or fumaric acid units. It is intendedthat references herein to PBS copolymers comprising malic acid includeimplants where the malic acid in the PBS copolymer has undergone furtherreaction during processing, for example, to form maleic or fumaric acidor another compound. Thus, implants comprising poly(butylenesuccinate)-malic acid copolymer refer to implants prepared fromcopolymers comprising succinic acid, 1,4-butanediol and malic acid. Inanother preferred embodiment, malic acid may be used as a branching orcross-linking agent to prepare a copolymer of poly(butylene succinate)with adipate, which may be referred to aspoly[(butylenesuccinate)-co-adipate] cross-linked with malic acid. Themalic acid disclosed herein may be the L-enantiomer, D-enantiomer, acombination therefore, but in one preferred embodiment the poly(butylenesuccinate) is prepared using L-malic acid, such that poly(1,4-butyleneglycol-co-succinic acid), cross-linked with L-malic acid is oneparticularly preferred composition.

Agents that may be used to chain extend poly(butylene succinate) orcopolymer thereof also include epoxides, isocyanates, diisocyanates,oxazolines, diepoxy compounds, acid anhydrides, carbonates, silicateesters, and carbodiimides. Additional monomers may also be included thatcan be cross-linked, for example, maleic, fumaric, and itaconic acidscan be incorporated and chains extended by the addition of peroxide. Inone embodiment, copolymers with long-chain branching are preferred. Itshould be noted however that the use of isocyanates and diisocyanates isnot preferred due to the toxicity associated with the use of thesecross-linking chemistries. In one embodiment, the PBS and copolymerpolymeric compositions exclude compositions prepared with isocyanates ordiisocyanates. In another embodiment, the PBS and copolymer polymericcompositions exclude compositions prepared with urethane linkages. In aparticularly preferred composition, the PBS and copolymer polymericcompositions used herein to prepare the implants are prepared only frommonomers that have one or more of the following groups: hydroxy groupsand carboxylic acid groups. In another embodiment, the PBS and copolymerthereof polymeric compositions exclude ether linkages.

In a preferred embodiment, the poly(butylene succinate) and copolymersthereof contain at least 70%, more preferably 80%, and even morepreferably 90% by weight succinic acid and 1,4-butanediol units.

In another embodiment, the poly(butylene succinate) and copolymersthereof disclosed herein include polymers and copolymers in which knownisotopes of hydrogen, carbon and/or oxygen are enriched. Hydrogen hasthree naturally occurring isotopes, which include ¹H (protium), ²H(deuterium) and ³H (tritium), the most common of which is the ¹Hisotope. The isotopic content of the polymer or copolymer can beenriched for example, so that the polymer or copolymer contains a higherthan natural ratio of a specific isotope or isotopes. The carbon andoxygen content of the polymer or copolymer can also be enriched tocontain higher than natural ratios of isotopes of carbon and oxygen,including, but not limited to ¹³C_(,) ¹⁴C_(,) ¹⁷O or ¹⁸O. Other isotopesof carbon, hydrogen and oxygen are known to one of ordinary skill in theart. A preferred hydrogen isotope enriched in polybutylene succinate) orcopolymer thereof is deuterium, i.e., deuterated poly(butylenesuccinate) or copolymer thereof. The percent deuteration can be up to atleast 1% and up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 65, 70,75, 80, or 85% or greater.

Preferred polymers and copolymers have a weight average molecular weight(Mw) of 10,000 to 400,000, more preferably 50,000 to 300,000 and evenmore preferably 100,000 to 200,000 based on gel permeationchromatography (GPC) relative to polystyrene standards. In aparticularly preferred embodiment the polymers and copolymers have aweight average molecular weight of 50,000 to 300,000, and morepreferably 75,000 to 300,000.

In a preferred embodiment, the tensile strength of an unoriented form ofpoly(butylene succinate) or copolymer thereof that is used to make theimplants should be at least 1 MPa, preferably 10 MPa, more preferably 35MPa, and even more preferably up to 70 MPa or higher. A particularlypreferred tensile range for unoriented forms is 35-60 MPa. The Young'smodulus of an unoriented form of poly(butylene succinate) or copolymerthereof that is used to make the implants should preferably be in therange of 30-700 MPa, and more preferably 300-500 MPa depending on itscrystallinity. It is also preferable that the polymer or copolymer has amelting point of at least 80° C., preferably 90° C., and even morepreferably greater than 100° C. In a preferred embodiment, the meltingpoint of the poly(butylene succinate) or copolymer thereof that is usedto make the implants is 115° C.±20° C., and more preferably between 105°C. and 120° C. A higher melting point (over 100° C.) is preferable toprovide improved stability of the implants particularly duringsterilization, shipping and storage.

In one preferred embodiment, the poly(butylene succinate) or copolymerthereof used to make the implants has one or more, or all of thefollowing properties: density of 1.23-1.26 g/cm³, glass transitiontemperature of −31 C. to −35° C., melting point of 113° C. to 117° C.,melt flow rate (MFR) at 190° C./2.16 kgf of 2 to 10 g/10 min, andtensile strength of 30 to 60 MPa.

In a particularly preferred embodiment, it is important that thepoly(butylene succinate) or copolymer thereof, has a low moisturecontent during processing and storage. This is necessary to ensure thatthe implants can be produced with high tensile strength, prolongedstrength retention, and good shelf life. In a preferred embodiment, thepolymers and copolymers that are used to prepare the implants have amoisture content of less than 1,000 ppm (0.1 wt %), less than 500 ppm(0.05 wt %), less than 300 ppm (0.03 wt %), more preferably less than100 ppm (0.01 wt %), and even more preferably less than 50 ppm (0.005 wt%).

The compositions used to prepare the implants must have a low endotoxincontent. The endotoxin content must be low enough so that the implantsproduced from the poly(butylene succinate) or copolymer thereof have anendotoxin content of less than 20 endotoxin units per device asdetermined by the limulus amebocyte lysate (LAL) assay. In oneembodiment, the compositions have an endotoxin content of <2.5 EU/g ofPBS or copolymer thereof.

B. Additives and Other Polymers

Certain additives may be incorporated into poly(butylene succinate) andcopolymers thereof prior to converting these compositions intoresorbable implants. Preferably, these additives are incorporated duringthe compounding process to produce pellets that can be subsequentlyprocessed into implants. For example, additives may be compounded withpoly(butylene succinate) or copolymer thereof, the compoundedpoly(butylene succinate) or copolymer thereof extruded into pellets, andthe pellets 3D printed or extruded into fibers suitable for makingimplantable surgical meshes, for example by knitting, weaving or 3Dprinting. In another embodiment, the additives may be incorporated usinga solution-based process. In a preferred embodiment of the invention,the additives are biocompatible, and even more preferably the additivesare both biocompatible and resorbable.

In one embodiment of the invention, the additives may be nucleatingagents and/or plasticizers. These additives may be added in sufficientquantity to produce the desired result. In general, these additives maybe added in amounts of up to 20% by weight. Nucleating agents may beincorporated to increase the rate of crystallization of thepoly(butylene succinate) or copolymer thereof. Such agents may be used,for example, to improve the mechanical properties of fibers and meshes,as well as the implants, and to reduce cycle times. Preferred nucleatingagents include, but are not limited to, salts of organic acids such ascalcium citrate, polymers or oligomers of poly(butylene succinate)polymers and copolymers, high melting polymers such as polyglycolic andpolylactic acids, alpha-cyclodextrin, talc, micronized mica, calciumcarbonate, ammonium chloride, and aromatic amino acids such as tyrosineand phenylalanine.

Plasticizers that may be incorporated into the compositions include, butare not limited to, di-n-butyl maleate, methyl laureate, dibutylfumarate, di(2-ethylhexyl) (dioctyl) maleate, paraffin, dodecanol, oliveoil, soybean oil, polytetramethylene glycols, methyl oleate, n-propyloleate, tetrahydrofurfuryl oleate, epoxidized linseed oil, 2-ethyl hexylepoxytallate, glycerol triacetate, methyl linoleate, dibutyl fumarate,methyl acetyl ricinoleate, acetyl tri(n-butyl) citrate, acetyl triethylcitrate, tri(n-butyl) citrate, triethyl citrate, bis(2-hydroxyethyl)dimerate, butyl ricinoleate, glyceryl tri-(acetyl ricinoleate), methylricinoleate, n-butyl acetyl rincinoleate, propylene glycol ricinoleate,diethyl succinate, diisobutyl adipate, dimethyl azelate, di(n-hexyl)azelate, tri-butyl phosphate, and mixtures thereof. Particularlypreferred plasticizers are citrate esters.

In another preferred embodiment of the invention, the additives arecontrast agents, radiopaque markers and radioactive substances. Theseadditives may also be incorporated into poly(butylene succinate) orcopolymer thereof either before preparing the implants, such as fibers,meshes or 3D printed objects, or after they are prepared.

In yet another embodiment of the invention, the additives are otherpolymers, preferably other resorbable polymers. Examples of otherresorbable polymers that can be incorporated into the compositions usedto make the implants are: polymers and copolymers of glycolic acid,lactic acid, 1,4-dioxanone, trimethylene carbonate, ε-caprolactone,3-hydroxybutyrate, 4-hydroxybutyrate, including polyglycolic acid,polylactic acid, polydioxanone, polycaprolactone, poly-4-hydroxybutyrateand copolymers thereof, poly-3-hydroxybutyrate, copolymers of glycolicand lactic acids, such as VICRYL® polymer, MAXON® and MONOCRYL®polymers, and including poly(lactide-co-caprolactones);poly(orthoesters); polyanhydrides; poly(phosphazenes); synthetically orbiologically prepared polyesters; polycarbonates; tyrosinepolycarbonates; polyamides (including synthetic and natural polyamides,polypeptides, and poly(amino acids)); polyesteramides; poly(alkylenealkylates); polyethers (such as polyethylene glycol, PEG, andpolyethylene oxide, PEO); polyvinyl pyrrolidones or PVP; polyurethanes;polyetheresters; polyacetals;

polycyanoacrylates; poly(oxyethylene)/poly(oxypropylene) copolymers;polyacetals, polyketals; polyphosphates; (phosphorous-containing)polymers; polyphosphoesters; polyalkylene oxalates; polyalkylenesuccinates; poly(maleic acids); silk (including recombinant silks, andsilk derivatives and analogs); chitin; chitosan; modified chitosan;biocompatible polysaccharides; hydrophilic or water soluble polymers,such as polyethylene glycol, (PEG) or polyvinyl pyrrolidone (PVP), withblocks of other biocompatible or biodegradable polymers, for example,poly(lactide), poly(lactide-co-glycolide, or polycaprolcatone andcopolymers thereof, including random copolymers and block copolymersthereof.

In one embodiment, the PBS or copolymer thereof polymeric composition isnot blended with another polymer. In another embodiment, the PBS orcopolymer thereof polymeric composition is not blended with polylacticacid (PLA).

C. Bioactive Agents

If desired, the implants of polybutylene succinate and copolymersthereof may incorporate bioactive agents. These bioactive agents may beadded during the formulation process, during pelletization or blending,or may be added later to the implants.

Examples of bioactive agents that can be incorporated into the implantsof poly(butylene succinate) or copolymer thereof, include, but are notlimited to, small-molecule drugs, anti-inflammatory agents,immunomodulatory agents, molecules that promote cell migration,molecules that promote or retard cell division, molecules that promoteor retard cell proliferation and differentiation, molecules thatstimulate phenotypic modification of cells, molecules that promote orretard angiogenesis, molecules that promote or retard vascularization,molecules that promote or retard extracellular matrix disposition,signaling ligands, platelet rich plasma, peptides, proteins,glycoproteins, anesthetics, hormones, antibodies, antibiotics,antimicrobials, growth factors, fibronectin, laminin, vitronectin,integrins, steroids, hydroxyapatite, silver particles, vitamins,non-steroidal anti-inflammatory drugs, chitosan and derivatives thereof,alginate and derivatives thereof, collagen, sugars, polysaccharides,nucleotides, oligonucleotides, lipids, lipoproteins, anti-adhesionagents, hyaluronic acid and derivatives thereof, allograft material,xenograft material, ceramics, nucleic acid molecules, antisensemolecules, aptamers, siRNA, nucleic acids, and combinations thereof. Ina particularly preferred embodiment, the implants designed to allowtissue in-growth on one surface of the implant, and prevent tissuein-growth on another surface may be coated on the surfaces where tissuein-growth is not desired with a Sepra® hydrogel barrier. Such implantsmay be used, for example, in hernia repair to minimize tissue attachmentto the visceral side of the implant following intraabdominal placement.

Antimicrobial agents that may be incorporated into the implants ofpoly(butylene succinate) and copolymers thereof, include, but are notlimited to, antibacterial drugs, antiviral agents, antifungal agents,and antiparisitic drugs. Antimicrobial agents include substances thatkill or inhibit the growth of microbes such as microbicidal andmicrobiostatic agents. Antimicrobial agents that may be incorporatedinto the implants of poly(butylene succinate) and copolymers thereof,include, but are not limited to: rifampin; minocycline and itshydrochloride, sulfate, or phosphate salt; triclosan; chlorhexidine;vancomycin and its hydrochloride, sulfate, or phosphate salt;tetracycline and its hydrochloride, sulfate, or phosphate salt, andderivatives; gentamycin; cephalosporin antimicrobials; aztreonam;cefotetan and its disodium salt; loracarbef; cefoxitin and its sodiumsalt; cefazolin and its sodium salt; cefaclor; ceftibuten and its sodiumsalt; ceftizoxime; ceftizoxime sodium salt; cefoperazone and its sodiumsalt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil;ceftazidime; cefotaxime and its sodium salt; cefadroxil; ceftazidime andits sodium salt; cephalexin; cefamandole nafate; cefepime and itshydrochloride, sulfate, and phosphate salt; cefdinir and its sodiumsalt; ceftriaxone and its sodium salt; cefixime and its sodium salt;cefpodoxime proxetil; meropenem and its sodium salt; imipenem and itssodium salt; cilastatin and its sodium salt; azithromycin;clarithromycin; dirithromycin; erythromycin and hydrochloride, sulfate,or phosphate salts, ethylsuccinate, and stearate forms thereof,clindamycin; clindamycin hydrochloride, sulfate, or phosphate salt;lincomycin and hydrochloride, sulfate, or phosphate salt thereof,tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicillin and its sodium salt; clavulanic acid and itssodium or potassium salt; penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;ticarcillin and its disodium salt; sulbactam and its sodium salt;moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin;gatifloxacin; trovafloxacin mesylate; alatrofloxacin mesylate;trimethoprim; sulfamethoxazole; demeclocycline and its hydrochloride,sulfate, or phosphate salt; doxycycline and its hydrochloride, sulfate,or phosphate salt; oxytetracycline and its hydrochloride, sulfate, orphosphate salt; chlortetracycline and its hydrochloride, sulfate, orphosphate salt; metronidazole; dapsone; atovaquone; rifabutin;linezolide; polymyxin B and its hydrochloride, sulfate, or phosphatesalt; sulfacetamide and its sodium salt; clarithromycin; and silverions, salts, and complexes. In a preferred embodiment, the antimicrobialagents incorporated into the implants are (i) rifampin and (ii)minocycline and its hydrochloride, sulfate, or phosphate salt. In aparticularly preferred embodiment the implants of poly(butylenesuccinate) and copolymer thereof comprise rifampin and minocycline orits hydrochloride, sulfate, or phosphate salt.

III. Methods Of Synthesizing and Processing Implants of POLY(BUTYLENESUCCINATE) and Copolymers Thereof A. Poly(butylene succinate) andCopolymers Thereof

Poly(butylene succinate) and copolymers thereof may be synthesized byany suitable method. A suitable method must provide a biocompatiblepolymeric composition of PBS and copolymer thereof. In an embodiment,poly(butylene succinate) can be synthesized by (i) esterification ofsuccinic acid and 1,4-butanediol or transesterification of dimethylsuccinate and 1,4-butanediol to obtain oligomers, and (ii)polycondensation of the oligomers to form high weight average molecularweight poly(butylene succinate).

In one method, poly(butylene succinate) may be prepared by charging asuitable vessel with succinic acid (or dimethyl succinate) and1,4-butanediol in a 1:1 ratio (or with a small excess of1,4-butanediol). The reactants are heated to 130-190° C., morepreferably 160-190° C., under an inert atmosphere, to melt the acidcomponent and distill off water (or methanol). Once the distillation iscompleted, the pressure in the vessel is reduced using a high vacuum,and a suitable high weight average molecular weight poly(butylenesuccinate) is produced by polycondensation preferably at a temperatureof 220-240° C. in the presence of a catalyst.

Suitable catalysts for the synthesis of poly(butylene succinate) includep-toluenesulfonic acid, tin (II) chloride, monobutyl tin oxide,tetrabutyl titanate, tetraisoproypl titanate, lanthanide triflates, anddistannoxane. Catalysts may include metal elements of the Groups 1 to 14of the periodic table. Preferred catalysts have metal elements that arescandium, yttrium, titanium, zirconium, vanadium, molybdenum, tungsten,zinc, iron and germanium. Titanium and zirconium catalysts areparticularly preferred for preparing poly(butylene succinate) andcopolymers thereof. Tetraalkyl titanates are preferred catalysts.Specifically, tetra-n-propyl titanate, tetraisopropyl titanate,tetra-n-butyl titanate, tetra-t-butyl titanate, tetraphenyl titanate,tetracyclohexyl titanate, tetrabenzyl titanate, and mixed titanatesthereof are preferred. In addition, titanium (oxy)acetylacetonate,titanium tetraacetylacetonate, titanium (diisopropoxide)acetylacetonate, titanium bis(ammonium lactate) dihydroxide, titaniumbis(ethylacetoacetate) diisopropoxide, titanium (triethanolaminate)isopropoxide, polyhydroxytitanium stearate, titanium lactate, titaniumtriethanolaminate, butyl titanate dimer, are also preferred catalysts.Of these, tetra-n-propyl titanate, tetraisopropyl titanate, andtetra-n-butyl titanate, titanium (oxy)acetylacetonate, titaniumtetraacetylacetonate, titanium bis(ammonium lactate) dihydroxide,polyhydroxytitanium stearate, titanium lactate, and butyl titanate dimerare preferred, and tetra-n-butyl titanate, titanium(oxy)acetylacetonate, titanium tetraacetylacetonate, polyhydroxytitaniumstearate, titanium lactate, and butyl titanate dimer are more preferred.Particularly, tetra-n-butyl titanate, polyhydroxytitanium stearate,titanium (oxy)acetylacetonate, and titanium tetraacetylacetonate arepreferred. Zirconium catalysts that may be used to prepare the polymeror copolymer include zirconium tetraacetate, zirconium acetatehydroxide, zirconium tris(butoxy) stearate, zirconyl diacetate,zirconium oxalate, zirconyl oxalate, zirconium potassium oxalate,polyhydroxyzirconium stearate, zirconium ethoxide, zirconiumtetra-n-propoxide, zirconium tetraisopropoxide, zirconiumtetra-n-butoxide, zirconium tetra-t-butoxide, zirconium tributoxyacetylacetonate, and mixtures thereof. Of these, zirconyl diacetate,zirconium tris(butoxy) stearate, zirconium tetraacetate, zirconiumacetate hydroxide, zirconium ammonium oxalate, zirconium potassiumoxalate, polyhydroxyzirconium stearate, zirconium tetra-n-propoxide,zirconium tetraisopropoxide, zirconium tetra-n-butoxide, and zirconiumtetra-t-butoxide are preferred, and zirconyl diacetate, zirconiumtetraacetate, zirconium acetate hydroxide, zirconium tris(butoxy)stearate, zirconium ammonium oxalate, zirconium tetra-n-propoxide, andzirconium tetra-n-butoxide are more preferred. Particularly, zirconiumtris(butoxy) stearate is preferred. Germanium catalysts that may be usedinclude inorganic germanium compounds such as germanium oxide andgermanium chloride and organic germanium compounds such astetraalkoxygermanium. Germanium oxide, tetraethoxygermanium,tetrabutoxygermanium, and the like are preferred. Other metal-containingcatalysts that can be used include scandium compounds such as scandiumcarbonate, scandium acetate, scandium chloride, and scandiumacetylacetonate, yttrium compounds such as yttrium carbonate, yttriumchloride, yttrium acetate, and yttrium acetylacetonate, vanadiumcompounds such as vanadium chloride, vanadium oxide trichloride,vanadium acetylacetonate, and vanadium acetylacetonate oxide, molybdenumcompounds such as molybdenum chloride and molybdenum acetate, tungstencompounds such as tungsten chloride, tungsten acetate, tungstenic acid,lanthanoid compounds such as cerium chloride, samarium chloride, andytterbium chloride.

When a metal compound is used as a catalyst, the amount of catalyst usedto prepare poly(butylene succinate) or copolymer thereof is preferably0.1 ppm or more, preferably 0.5 ppm or more, more preferably 1 ppm ormore, and less than 30,000 ppm, preferably less than 1,000 ppm, morepreferably less than 250 ppm, and more preferably less than 130 ppm.

After completion of the polycondensation, the polymer can be purified bydissolution in a solvent, filtering, and precipitation. For example, thepolymer can be dissolved in chloroform, filtered, and precipitated withan alcohol such as methanol or ethanol. If desired, the polymer may befurther purified by washing, for example with diethyl ether. Preferablythe amount of metal in the poly(butylene succinate) or copolymer thereofis less than 100 ppm, and more preferably less than 50 ppm. A preferredmetal content in the poly(butylene succinate) or copolymer thereof is0.1-100 ppm, and more preferably 1-50 ppm.

In an embodiment, the polymeric compositions of PBS and copolymerthereof used to prepare the implants comprise 1-500 ppm of one or moreof the following: silicon, titanium and zinc. Preferably, the polymericcompositions comprise less than 50 ppm of silicon, titanium and zinc. Inanother embodiment, the polymeric compositions used to make the implantsdo not comprise metals other than silicon, titanium and zinc indetectable quantities by PIXE analysis. In a particularly preferredembodiment, the polymeric compositions used to make the implants excludetin.

Copolymers of poly(butylene succinate) may be formed by copolymerizationwith different comonomer units, preferably dicarboxylic acids and diols,including for example, adipic acid, terephthalic acid, fumaric acid,ethylene glycol and 1,3-propanediol. Other suitable diol anddicarboxylic acid comonomer units include 1,2-propanediol,1,2-butanediol, 1,3-butanediol, 2,3-butanediol, 1,5-pentane diol,1,2-pentanediol, 2,4-pentanediol, 1,6-hexanediol, 1,2-hexanediol,suberic acid, sebacic acid, azelaic acid, decanedicarboxylic acid,dodecanedicarboxylic acid, and octadecanedicarboxylic acid. In apreferred embodiment, the content of comonomer units is less than 30%,more preferably less than 20% and even more preferably less than 15%. Inanother preferred embodiment, the comonomer content of the copolymer isless than 15%, and the melting point of the comonomer is more than 100°C. Preferably, the melting point of the PBS copolymer is between 105° C.and 120° C.

In yet another embodiment, the polymers and copolymers of succinic acidand 1,4-butanediol may contain chain branches, most preferably chainbranches formed with aliphatic oxycarboxylic acids. Preferred chainbranching agents are trifunctional and tetrafunctional aliphaticoxycarboxylic acids. Preferred trifunctional oxycarboxylic acid chainbranching agents may have (i) two carboxyl groups and one hydroxyl groupin the same molecule (such as malic acid), or (ii) one carboxyl groupand two hydroxyl groups in the same molecule. Preferred tetrafunctionaloxycarboxylic acid chain branching agents may have (i) three carboxylgroups and one hydroxyl group in the same molecule (such as citricacid), (ii) two carboxyl groups and two hydroxyl groups in the samemolecule (such as tartaric acid), or (iii) three hydroxyl groups and onecarboxyl group in the same molecule. Other chain branching agents thatmay be incorporate include hydroxyglutaric acid, hydroxymethylglutaricacid, hydroxyisophthalic acid, and hydroxyterephthalic acid. Malic acid,tartartic acid and citric acid are particularly preferred chainbranching agents. Chain branching agents, cross-linking agents, couplingagents and chain extending agents are preferably incorporated into thepoly(butylene succinate) and copolymer thereof in amounts of 0.01 to 5.0mol %, more preferably 0.01 to 2.5 mol %, and most preferably 0.1 to 0.5mol %. In one embodiment, the chain branching agent is malic acid. In apreferred embodiment, malic acid is incorporated in the poly(butylenesuccinate) polymer or copolymer in an amount of 0.01-5.0 mol %, morepreferably 0.1-0.5 mol %, or in an amount of 0.01-1 part by weight, morepreferably 0.1-0.5 parts by weight. When malic acid is used as atrifunctional oxycarboxylic acid serving as the copolymerizablecomponent, examples of the copolyester include succinicacid-1,4-butanediol-malic acid copolyester, succinic acid-adipicacid-1,4-butanediol-malic acid copolyester, succinicacid-1,4-butanediol-malic acid-tartaric acid copolyester, succinicacid-adipic acid-1,4-butanediol-malic acid-tartaric acid copolyester,succinic acid-1,4-butanediol-malic acid-citric acid copolyester, andsuccinic acid-adipic acid-1,4-butanediol-malic acid-citric acidcopolyester. Malic acid may be present as the L-enantiomer,D-enantiomer, or both, but L-malic acid is preferred. During exposure toheat, or further processing, the malic acid monomers in the copolymermay dehydrate to produce fumaric and maleic acids monomers in thecopolymer. Thus, the implant disclosed herein may also comprise fumaricand maleic acid units, or combinations thereof.

B. Spinning of Poly(butylene succinate) and Copolymers Thereof

Poly(butylene succinate) and copolymers thereof may be processed andoriented to provide implants with high tensile strength and prolongedstrength retention. The polymers may be processed in the melt or insolution. In one preferred embodiment, poly(butylene succinate) andcopolymers thereof are melt processed.

In melt processing of poly(butylene succinate) and copolymers thereof itis important to prevent hydrolysis of the polymers by residual moisture.Therefore, it is important that the polymers are dried prior to meltprocessing. In a preferred embodiment, the poly(butylene succinate) andcopolymers are dried prior to melt processing so that they have amoisture content of less than 0.1 wt. %, preferably less than 0.05 wt.%, more preferably less than 0.01 wt. %, and even more preferably lessthan 0.005 wt. %. The polymers may be dried with hot air and undervacuum prior to melt processing. In a preferred embodiment, the polymersare dried under vacuum at 30-90° C., more preferably 60-90° C.

In order to obtain implants with high tensile strength and prolongedstrength retention, it is important to prevent loss of weight averagemolecular weight during melt processing of poly(butylene succinate) andcopolymers thereof. At temperatures in excess of 200° C., the shearviscosity of poly(butylene succinate) can decrease significantly. Themagnitude of the loss increases as the temperature rises above 200° C.and as the exposure time increases. In order to make implants with thehighest tensile strength and prolonged strength retention, it istherefore important to minimize the time the polymers are exposed tohigh processing temperatures as well as the presence of moisture in thepolymers. In an embodiment, the implants are melt extruded with atemperature profile of 60-230° C., more preferably 80-180° C., and evenmore preferably 80-170° C.

Examples 1 and 2 described herein compare two different methods of meltextruding poly(butylene succinate) and copolymers thereof. It has beendiscovered that the method disclosed in Example 2 yields fibers withsubstantially higher tensile strengths than those obtained by the methoddescribed in Example 1. Thus, the method disclosed in Example 2 ispreferred for making implants comprising fibers when it is desirable forthe fibers to have high tensile strength and prolonged strengthretention. Using the method disclosed in Example 2, fibers were obtainedwith tensile strengths of 779-883 MPa compared to tensile strengths of434-518 MPa produced by the method disclosed in Example 1. In contrastto the method of Example 1, the use of multi-stage incrementalorientation of the fiber and use of conductive chambers, instead ofstandard convention chambers used in Example 1, resulted in fiber withsurprisingly higher tensile strengths. In a preferred embodiment,monofilament or multifilament fiber comprising poly(butylene succinate)and copolymers thereof is produced by a method comprising the steps of:(a) spinning multifilament or monofilament fiber comprising the polymercomposition, (b) one or more stages of drawing the multifilament ormonofilament fiber with an orientation ratio of at least 3.5 at atemperature of 50-70° C., (c) one or more stages of drawing themultifilament or monofilament fiber with an orientation ratio of atleast 2.0 at a temperature of 65-75° C., and (d) drawing themultifilament or monofilament fiber with an orientation ratio greaterthan 1.0 at a temperature of 70-75° C. Preferably, the sum of theorientation ratios is over 6.0, 6.5, 7.0, 7.5 or 8.0. In an even morepreferred embodiment, the fibers are drawn in a conductive liquidchamber. Prior to drawing the fibers, melt extruded polymer ispreferably quenched in a conductive liquid bath. The temperature of thebath is preferably from 50° C. to 70° C. Further cooling of the fiberafter it is quenched may be desired, and can be achieved by passing thefiber between two godets. In an embodiment, the temperature range forextrusion of PBS or copolymer thereof to form high strength fibers isfrom 60-230° C., or 75-220° C., but is more preferably from 75-200° C.,80-180° C., 80-175° C., or 80-170° C. Example 3 discloses specificexamples of a method using multi-stage incremental orientation and theuse of conductive chambers to prepare multifilament fibers of PBS andcopolymers thereof. Examples of multifilament fibers with tenacities of8.3-12.5 g/d are shown.

If desired, the oriented fibers may be annealed. In one embodiment, theoriented fibers may be annealed using temperatures of 80° C. to 120° C.,and more preferably 105° C±10° C.

In an embodiment, the oriented monofilament fibers have diametersranging from 0.01 to 1.00 mm. In a particularly preferred embodiment,the diameters of the monofilament fibers range from 0.07 to 0.7 mm. Inanother embodiment, the monofilament fibers may optionally meet the USPstandards for absorbable monofilament sutures.

In an embodiment, the monofilament fibers of PBS and copolymers thereofhave a tensile strength of 400 MPa to 2,000 MPa, and more preferably atensile strength greater than 500 MPa, 600 MPa, 700 MPa or 800 MPa, butless than 1,200 MPa. In another embodiment, the monofilament fibers ofPBS and copolymer thereof have a Young's Modulus of at least 600 MPa,and less than 3 GPa, but more preferably greater than 800 MPa, 1 GPa,1.5 GPa, and 2 GPa. In a further embodiment, the monofilament fibers ofPBS and copolymer thereof have an elongation to break of 10-150%, andmore preferably 10-50%.

In yet another embodiment, the multifilament fibers of PBS andcopolymers thereof have a tenacity greater than 4 grams per denier, butless than 14 grams per denier. Preferably, the multifilament fibers havean elongation to break of between 15% and 50%.

The yarns and monofilament fibers of poly(butylene succinate) andcopolymers thereof may be used to prepare knitted and woven meshes,non-woven meshes, suture tapes, mesh sutures, webs, and patches. Thesemesh, web, and patch products are particularly useful for soft tissuerepair, hernia repair, breast lifts, breast reconstructions, face andneck lifts, pelvic floor reconstruction, treatment of stress urinaryincontinence, organ salvage, lift and suspension procedures, and formaking enclosures, pouches, holders, covers, clamshells, and casings tohold implantable medical devices.

In view of their mechanical properties, the yarns and monofilamentfibers disclosed herein may also be used to prepare medical devicesincluding sutures, braided sutures, hybrid sutures of monofilament andmultifilament fibers, barbed sutures, suture tapes, mesh sutures,braids, ligatures, tapes, knitted or woven meshes, knitted tubes,multifilament meshes, patches, wound healing devices, bandages, wounddressings, burn dressings, ulcer dressings, skin substitutes, hemostats,tracheal reconstruction devices, organ salvage devices, duralsubstitutes, dural patches, nerve regeneration or repair devices, herniarepair devices, hernia meshes, hernia plugs, device for temporary woundor tissue support, tissue engineering scaffolds, guided tissuerepair/regeneration devices, anti-adhesion membranes, adhesion barriers,tissue separation membranes, retention membranes, slings, devices forpelvic floor reconstruction, urethral suspension devices, devices fortreatment of urinary incontinence, devices for treatment ofvesicoureteral reflux, bladder repair devices, sphincter muscle repairdevices, suture anchors, soft suture anchors, bone anchors, ligamentrepair devices, ligament augmentation devices, ligament grafts, anteriorcruciate ligament repair devices, tendon repair devices, tendon grafts,tendon augmentation devices, rotator cuff repair devices, meniscusrepair devices, meniscus regeneration devices, articular cartilagerepair devices, osteochondral repair devices, spinal fusion devices,stents, including coronary, cardiovascular, peripheral, ureteric,urethral, urology, gastroenterology, nasal, ocular, or neurology stents,stent grafts, cardiovascular patches, vascular closure devices,intracardiac septal defect repair devices, including but not limited toatrial septal defect repair devices and PFO (patent foramen ovale)closure devices, left atrial appendage (LAA) closure devices,pericardial patches, vein valves, heart valves, vascular grafts,myocardial regeneration devices, periodontal meshes, guided tissueregeneration membranes for periodontal tissue, embolization devices,anastomosis devices, cell seeded devices, controlled release devices,drug delivery devices, plastic surgery devices, breast lift devices,mastopexy devices, breast reconstruction devices, breast augmentationdevices (including devices for use with breast implants), breastreduction devices (including devices for removal, reshaping andreorienting breast tissue), devices for breast reconstruction followingmastectomy with or without breast implants, facial reconstructivedevices, forehead lift devices, brow lift devices, eyelid lift devices,face lift devices, rhytidectomy devices, thread lift devices (to liftand support sagging areas of the face, brow and neck), rhinoplastydevices, device for malar augmentations, otoplasty devices, neck liftdevices, mentoplasty devices, buttock lift devices, cosmetic repairdevices, devices for facial scar revision, and enclosures, pouches,holders, covers, clamshells, casings to hold implantable medicaldevices.

C. 3D Printing of Implants

In another preferred embodiment, the implants may be prepared by 3Dprinting. Methods that can be used to 3D print poly(butylene succinate)and copolymers thereof include fused filament fabrication (FFF), fusedpellet deposition, melt extrusion deposition (MED), selective lasermelting, and solution printing.

A particularly preferred method of 3D printing poly(butylene succinate)and copolymers thereof is to feed a filament of the polymer or copolymerto a FFF printer. In FFF of poly(butylene succinate) and copolymers itis important to prevent hydrolysis of the polymers by residual moisture.Therefore, it is important that the filament used in FFF has a lowmoisture content, preferably less than 0.1 wt. %, preferably less than0.05 wt. %, more preferably less than 0.01 wt. %, and even morepreferably less than 0.005 wt. %. The filament may be dried with hot airand under vacuum prior to printing. In a preferred embodiment, thepolymers are dried under vacuum at 30-90° C., more preferably 60-90° C.

In order to obtain 3D printed implants with high tensile strength andprolonged strength retention, it is important to prevent loss of weightaverage molecular weight during melt processing of poly(butylenesuccinate) and copolymers thereof. The magnitude of the molecular weightloss increases as the temperature rises above 200° C. and as theexposure time increases. In order to make implants with the highesttensile strength and prolonged strength retention, it is thereforeimportant to minimize the time the polymers are exposed to highprocessing temperatures during 3D printing as well as the presence ofmoisture in the polymer or copolymer. The temperature of the hot end,including the printer nozzle, may be set to temperatures ranging from120° C. to 300° C., more preferably 130° C. to 230° C., and even morepreferably 150° C. to 200° C.

Methods of 3D Printing of PBS and copolymers thereof are shown inExamples 9 and 10. The 3D Printing of a PBS-malic acid copolymer by MEDusing different thermal conditions is shown in Example 18, and theproperties of the implants obtained shown in Table 17. Surprisingly, theweight average molecular weight of the PBS polymer was found to increaseas the processing temperature was raised from 180° C. to 220° C. (At230° C., the weight average molecular weight decreased from the peak at220° C.) An increase in molecular weight can be particularlyadvantageous in some implant applications. For example, increasing theweight average molecular weight can result in prolonged strengthretention of the implant. In an embodiment, implants comprising PBS andcopolymers thereof, are produced with weight average molecular weightsthat exceed the weight average molecular weights of the composition usedto prepare the implants. The implants may be formed by 3D Printing,including fused filament fabrication, fused pellet deposition, meltextrusion deposition, and selective laser melting, but also using otherthermal processing techniques, such as melt processing, melt extrusion,melt-blowing, melt spinning, injection molding, compression molding,lamination, foaming, film extrusion, thermoforming, pultrusion, molding,tube extrusion, spun-bonding, nonwoven fabrication. In an embodiment,implants comprising PBS and copolymers thereof, may be formed by meltprocessing with weight average molecular weights that are between 1-50%,more preferably 5-30%, higher than the weight average molecular weightsof the PBS and copolymers resins used to prepare the implants.

D. Other Methods of Manufacturing Implants

Implants comprising poly(butylene succinate) and copolymers thereof mayalso be prepared by casting, solvent casting, solution spinning,solution bonding of fibers, melt processing, extrusion, melt extrusion,melt spinning, fiber spinning, orientation, relaxation, annealing,injection molding, compression molding, lamination, particle formation,microparticle, macroparticle and nanoparticle formation, foaming, dryspinning, knitting, weaving, crocheting, melt-blowing, film formation,film blowing, film casting, membrane forming, electrospinning,thermoforming, pultrusion, centrifugal spinning, molding, tubeextrusion, spunbonding, nonwoven fabrication, entangling of staplefibers, fiber knitting, weaving and crocheting, mesh fabrication,coating, dip coating, laser cutting, barbing, barbing of fibers,punching, piercing, pore forming, lyophilization, stitching,calendering, freeze-drying, phase separation, particle leaching, thermalphase separation, leaching, latex processing, gas plasma treatment,emulsion processing, 3D printing, fused filament fabrication, fusedpellet deposition, melt extrusion deposition, selective laser melting,printing of slurries and solutions using a coagulation bath, andprinting using a binding solution and granules of powder.

E. Antimicrobial Coatings

In an embodiment, the implants comprising poly(butylene succinate) andcopolymers thereof, may be coated with solutions of antimicrobial agentsdissolved in poor solvents for poly(butylene succinate) and copolymersthereof. These poor solvents do not cause significant loss oforientation, if any, of the poly(butylene succinate) or copolymerthereof. However, these poor solvents allow the antimicrobial agents toslightly soften and penetrate the surfaces of the implants. This has twomain advantages. First, it allows the implants to be coated with higherconcentrations of antimicrobial agents, and second it allows theantimicrobial agents to diffuse into the implants. Diffusion of theantimicrobial agents into the implants results in a more prolongedrelease profile, and an increased ability of the implant to preventcolonization of the implants, and reduce or prevent the occurrence ofinfection following implantation in a patient. A suitable poor solventthat can dissolve antimicrobial agents, but not cause loss oforientation of the implants, is an aqueous or alcoholic solution oftetrahydrofuran (THF). Alcohols that may be combined with this solventincludes methanol and ethanol. The concentration of the antimicrobialagent(s) in the poor solvent can range from about 0.1 mg/mL to about 100mg/mL, preferably from about 1 mg/mL to about 30 mg/mL. The amount(density of coverage) of each antimicrobial coated on the implant canrange from about 1 μg/cm² to about 1000 μg/cm², or preferably, fromabout 50 μg/cm² to about 200 μg/cm². In various embodiments, the amountranges from about 10 μg/cm² to about 175 μg/cm², or from about 10μg/cm²to about 150 μg/cm², or from about 10 μg/cm² to about 100 μg/cm²,or from about 10 μg/cm² to about 75 mg/cm², or from about 20 μg/cm² toabout 200 μg/cm² or from about 50 μg/cm² to about 200 μg/cm², or fromabout 75 μg/cm² to about 200 μg/cm² or from about 100 μg/cm² to about200 μg/cm², or from about 150 μg/cm² to about 200 μg/cm².

In a preferred embodiment of the invention, the implants ofpoly(butylene succinate) and copolymers thereof, are coated withrifampin and minocycline (including its hydrochloride, sulfate, orphosphate salt) dissolved in poor solvents for poly(butylene succinate)and copolymers thereof. The antimicrobial agents may be applied to theoriented implants individually using the same or different poorsolvents, or from a single solution containing both antimicrobial agentsin a poor solvent. In one embodiment, rifampin may be applied to theimplants of poly(butylene succinate) and copolymers thereof fromsolutions of the following poor solvents (i) THF, (ii) DMSO, (iii) DMFand (iv) DMA each mixed with one or more of the following: water,methanol and/or ethanol. In another embodiment, minocycline may beapplied to the oriented implants of poly(butylene succinate) andcopolymers thereof from solutions in the following poor solvents:THF/water, THF/methanol, and THF/ethanol. In a preferred embodiment,rifampin and minocycline (including its hydrochloride, sulfate, orphosphate salt forms) are dissolved in a solution of THF/water,THF/ethanol or THF/ethanol, and applied to the implants.

F. Sterilization of the Implants

Implants made from the high tenacity yarns and monofilament fibers ofpoly(butylene succinate) and copolymers thereof, or from other implantsof poly(butylene succinate) and copolymers thereof, may be sterilizedusing ethylene oxide gas, and even more preferably using an ethyleneoxide cold cycle. In another preferred embodiment, the implants may besterilized with electron-beam irradiation or gamma-irradiation. Inanother embodiment, the implants may be sterilized using alcohol. Thesterility of the devices may be maintained by packaging of the devicesin packages designed to protect the devices from contamination andmaintain sterility.

IV. Implants Of POLY(BUTYLENE SUCCINATE) and Copolymers Thereof

The compositions of poly(butylene succinate) and copolymers thereofdescribed herein are suitable for preparing implants for soft and hardtissue repair, regeneration, and replacement.

Implants of oriented forms of poly(butylene succinate) and copolymersthereof are particularly suitable for use in applications requiringprolonged strength retention. The multifilament yarns and monofilamentfibers disclosed herein have prolonged strength in vivo making themsuitable for soft tissue repairs where high strength is required andwhere strength needs to be maintained for a prolonged period. Otherexamples of applications for the high strength yarn and monofilamentfibers include soft and hard tissue repair, replacement, remodeling, andregeneration include wound closure, breast reconstruction and breastlift, including mastopexy procedures, lift procedures performed on theface such as face-lifts, neck lifts, and brow lifts, ligament and othertendon repair procedures, abdominal closure, hernia repairs,anastomosis, slings for lifting tissues, slings for treatment of stressurinary incontinence, and pelvic floor reconstruction.

A. Sutures and Braids

It has been discovered that oriented fibers of PBS and copolymersthereof have prolonged strength retention when implanted in vivo, asshown in Examples 16 and 15. FIG. 5 is a SEM of an oriented fiber thathas been explanted after 4 weeks. Surprisingly, the surface of the fibershows little if any noticeable surface pitting or localized surfaceerosion at a 400× magnification. The result is surprising in view of theknown surface erosion and pitting of fibers derived from otherresorbable fibers. The finding makes it possible to use the fibers inapplications where prolonged strength retention is required. The lack ofsurface erosion is particularly important for strength retention ofsmall diameter fibers where pitting of the surface of the fiber canrapidly decrease strength retention. The fibers are also useful inapplications where high initial tensile strength is required. Example 16clearly shows that an oriented fiber, when implanted in vivo, does notlose a significant amount of tensile strength in the first 4 weeks. Thestudy described in Example 15 further demonstrates that a mesh made fromoriented fiber of PBS or copolymer thereof retains 74.1% of its strengthafter 12 weeks indicating prolonged strength retention of the fibers.Analysis of the weight average molecular weights of the implanted fibersafter 4 and 12 weeks in these studies shows that the fiber is degrading.The weight average molecular weight of the suture fiber in Example 16decreases 7.3% to 92.7% of the initial value at 4 weeks, and the weightaverage molecular weight of the fiber in the mesh decreases 25.9% to74.1% of the initial value at 12 weeks. It is also clear that there isgood correlation between the weight average molecular weight loss oforiented fibers of PBS and copolymers thereof in vitro, shown in Example12, with the in vivo data shown in Examples 15 and 16. This goodcorrelation is further evidence that the oriented fibers resist surfacepitting or surface erosion.

In a preferred embodiment, the weight average molecular weight of thefibers of PBS or copolymer thereof decrease 3 to 15% over a 4-weekperiod in vivo, 5% to 15% over an 8-week time period, or 10-35%, morepreferably 10-30%, over a 12-week time period, under physiologicalconditions, in vivo. The percent mass loss of the fibers is preferablybetween 0% and 5% over a 4-week period, under physiological conditions,in vivo.

In an embodiment, the monofilament fibers used to prepare sutures,suture meshes, braids, and tapes have a tensile strength between 400 MPaand 2,000 MPa, and more preferably greater than 500 MPa, 600 MPa, 700MPa or 800 MPa, and less than 1,200 MPa. Preferably the monofilamentfibers used to prepare the sutures, suture meshes and tapes have aYoung's Modulus between 600 MPa and 3 GPa, but preferably at least 800MPa, 1 GPa or 2 GPa. It has been found that the high Young's Modulus ofthe fiber prevents the suture from forming pig tails, or curling, duringsuturing. In another preferred embodiment, the monofilament fibers usedto prepare sutures, suture meshes, braids, and tapes have a meltingtemperature over 100° C., and preferably 105° C. to 120° C.

The monofilament fibers of poly(butylene succinate) and copolymersthereof may also be used to prepare high strength monofilament sutures,hybrid sutures of monofilament and multifilament fibers that have goodpliability, high knot strength, and can be securely knotted with lowprofile knot bundles (i.e. secured with a few throws). In oneembodiment, the monofilament fibers may be processed into resorbablehigh strength sutures and suture anchors that can be used, for example,in rotator cuff repair procedures. These sutures and anchors areparticularly useful for shoulder, elbow, wrist, hand hip, knee, ankle,and foot repairs, including tendon and ligament repairs, as well as insoft tissue approximation, ligation of soft tissue, abdominal closure,and plastic surgery procedures such as lift and suspension procedures,including face and breast lift procedures and breast reconstruction. Themonofilament sutures and suture anchors (including soft suture anchors)may incorporate one or more needles, be transparent or dyed, and ifdesired, braided as part of a suture or suture anchor, or braided intoflat tapes.

The monofilament fibers of poly(butylene succinate) and copolymersthereof may also be used to prepare barbed sutures.

It has been discovered that multifilament fiber of poly(butylenesuccinate) and copolymers thereof may be used to prepare high strengthmultifilament sutures, hybrid sutures of monofilament and multifilamentfibers that have excellent pliability, prolonged strength retention,high knot strength, good drape, and can be securely knotted forming softknot bundles with a low profile. Example 3 discloses one method that canbe used to produce high strength multifilament of PBS or copolymersthereof suitable for use in these applications.

Multifilament yarns of PBS and copolymers thereof may be processed intoresorbable high strength sutures and suture anchors that can be used inrotator cuff repair procedures. Currently, these procedures are repairedwith permanent sutures because existing resorbable sutures degrade tooquickly. In contrast to existing resorbable sutures, sutures preparedwith the high tenacity yarn of the present invention not only providehigh initial strength to stabilize a repair under a significant load,but also lose strength slowly allowing the repair of the soft tissues.The high strength sutures may also be used in bone anchors, sutureanchors, and soft suture anchors. These sutures and anchors areparticularly useful for shoulder, elbow, wrist, hand hip, knee, ankle,and foot repairs, including tendon and ligament repairs, as well as inlift and suspension procedures. The bone anchors, suture anchors andsoft suture anchors may incorporate one or more needles, yarns ofdifferent colors, and if desired, flat braided sections. The ability touse resorbable high tenacity sutures, suture anchors, bone anchors, andsoft suture anchors for procedures such as rotator cuff repaireliminates longer-term complications that can arise from foreign bodies,such as permanent sutures. These sutures may be used, for example, insoft tissue approximation, anastomosis, suspension and lift procedures,and for other applications in plastic surgery.

In one preferred embodiment, the yarns of poly(butylene succinate) andcopolymers thereof may be used to prepare high strength braided sutureswherein the breaking load of the sutures is between 40 N and 270 N. In aparticularly preferred embodiment, the high tensile strength braidedsutures comprising poly(butylene succinate) and copolymers thereof havea strength retention in vivo under physiological conditions of at least40% after implantation for 4-6 months.

Suture braids may be produced from the yarns with US Pharmacopeia (USP)suture sizes of 12-0, 11-0, 10-0, 9-0, 8-0, 7-0, 6-0, 5-0, 4-0, 3-0,2-0, 0, 1, 2, 3, 4, and 5, and meet the USP knot-pull tensile strengthsor breaking loads for these sizes. In another embodiment, the suturebraids may be oversized in diameter in order to meet USP knot-pulltensile strengths or breaking loads. For example, the diameter of thesuture braids maybe oversized by up to 0.3 mm, preferably 0.2 mm, morepreferably 0.1, and even more preferably 0.05 mm. The sutures may beneedled and/or contain loops at either end.

In another embodiment, the yarns of poly(butylene succinate) andcopolymers thereof and monofilaments of poly(butylene succinate) andcopolymers thereof, may be used to prepare flat suture tapes, includingflat braided suture tapes. These suture tapes are useful inapproximation and/or ligation of soft tissue, and are particularlyuseful in procedures requiring broad compression and increasedcut-through resistance. For example, the suture tapes can be used inshoulder and rotator cuff repair procedures such as acromioclavicularrepairs, and restoration of labral height in instability repairs, aswell as in ACL and PCL repair procedures. The suture tapes may have flatends, tapered ends, needles at one or both ends of the suture tape, andcomprise yarns with one or more different dyes.

Suture tapes disclosed herein may also be used as slings for tissuesupport, including slings for treatment of stress urinary incontinence.

In another embodiment, coatings may be applied to increase the lubricityof the braided sutures, and other fiber-based implants. These coatingsinclude wax, natural and synthetic polymers such as polyvinyl alcohol,and spin finishes including polyethylene glycol sorbitan monolaurate,and polymers or oligomers of ethylene oxide, propylene oxide, PEG400,PEG40 Stearate, Dacospin and Filapan. These coatings are preferablyapplied so the braided suture has a coating weight of less than 6 wt. %,more preferably less than 3 wt. %, and even more preferably less than 2wt. %. It is preferred that the coatings readily leave the surface ofthe braided suture or fiber-based device in vivo, for example, bydegradation or dissolution (for example if the coating iswater-soluble.)

In another embodiment, a coating may be applied to the surface of thesuture in order to slow degradation and increase strength retention invivo. For example, the suture may be coated with another polymer,preferably a slowly degrading polymer or composition, or coated withwax. For example, the suture may be coated with polycaprolactone to slowdegradation, and prolong strength retention further.

Braids (including suture tapes and suture braids) made from hightenacity yarns of poly(butylene succinate) and copolymers thereof arepreferably prepared by coating the yarn with spin finish, twisting orplying the yarn, and winding onto bobbins. Preferred spin finishes arepolyethylene glycol sorbitan monolaurate and polyethylene glycol. Thebobbins are then placed on a braider. The number of picks per inch maybe increased to improve the fineness of the braid, as desired. Thenumber of picks per inch can range from 5 to 100, and preferably 30 to60. In some embodiments, cores of monofilament, yarn, or multiple pliedyarn strands may be incorporated into the center of the braid.Alternatively, the braids may be prepared without cores. For example, toproduce hollow braids.

In an embodiment, the yarns and monofilament fibers of poly(butylenesuccinate) and copolymers thereof may be used to prepare mesh suturesthat can spread the load placed on re-apposed tissues, and therebyreduce suture pull-through (cheese wiring effect) and wound dehiscence.The mesh sutures may be threaded through tissue, the mesh anchored intissue under tension to re-appose soft tissue, and the needle removed.The use of mesh instead of suture fiber to re-appose tissues increasesthe strength of the repair. The porosity of the mesh is designed toallow the in-growth of tissue into the mesh.

The mesh sutures comprise a suture needle and a mesh component. The meshcomponent comprises fibers of poly(butylene succinate) and copolymersdescribed herein, and preferably monofilament fibers of poly(butylenesuccinate) and copolymers thereof. The mesh component is an interlacedstructure of fibers, preferably monofilament fibers of poly(butylenesuccinate) and copolymers thereof. Preferably the mesh structure isformed by knitting, braiding and weaving of fibers comprisingpoly(butylene succinate) and copolymers thereof, and most preferablymonofilament fibers. The cross-section of the mesh component may be anellipse, half-ellipse, circle, half-circle, gibbous, rectangle, square,crescent, pentagon, hexagon, concave ribbon, convex ribbon, H-beam,I-beam or dumbbell-shaped. Alternatively, the mesh component may assumethese shapes as it is passed through tissue. Preferably, the meshcomponent flattens as it is passed through tissue. The mesh componentmay also have a cross-sectional profile that varies over the length ofthe mesh. For example, part of the cross-section of the mesh may betubular, and another part non-tubular. However, in a preferredembodiment, the mesh has the same cross-section as the suture needle,and more preferably a cross-section with dimensions that are no morethan ±25% of the cross-section of the suture needle. The mesh preferablyhas pores with average diameters ranging from 5 μm to 5 mm, and morepreferably 50 μm to 1 mm. The width of the mesh is preferably from 1 mmto 20 mm, more preferably 1 mm to 10 mm, and even more preferably 1 mmto 7.8 mm. The width may vary along the length of the mesh. In anembodiment, the mesh may have an elasticity similar to the tissue at thesite of implantation. For example, in the case of the repair ofabdominal tissue, the mesh suture preferably has the same elasticity, ora similar elasticity to abdominal tissue. In another embodiment, theelasticity of the mesh is designed to permit even greater tension to beapplied to the re-apposed tissues in order to keep the re-apposed tissueapproximated to one another. Preferably, the mesh suture will stretchless than 30%, and more preferably less than 20%. It is also desirablethat the mesh has sufficient flexibility to allow it to be passedthrough tissues with tight curvatures. In a preferred embodiment, themesh suture has a stiffness less than 5 Taber Units (TU), morepreferably less than 1 TU, and even more preferably less than 0.8 TU. Inyet another embodiment, the mesh suture has an in vivo strengthretention under physiological conditions of at least 75% at 4 weeks,more preferably at least 80% at 4 weeks, and even more preferably atleast 65% at 12 weeks.

The sutures, braids, suture tapes, mesh sutures, meshes, patches andcircular knits made from the high tenacity yarns and monofilament fibersof poly(butylene succinate) and copolymers thereof may be used inligament and tendon repairs, hernia repairs, pelvic floorreconstruction, pelvic organ prolapse repair, Bankart lesion repair,SLAP lesion repair, acromion-clavicular repair, capsularshift/capsulolabral reconstruction, deltoid repair, Labral repair of theshoulder, Capsular/Labral Repairs of the Hip, rotator cuff tear repair,biceps tenodesis, foot and ankle medial/lateral repair andreconstruction, mid- and forefoot repair, Hallux valgus reconstruction,metatarsal ligament/tendon repair and reconstruction, Achilles tendonrepair, ulnar or radial collateral ligament reconstruction, lateralepicondylitis repair, biceps tendon reattachment, knee extra-capsularrepair, iliotibial band tenodesis, patellar tendon repair, VMOadvancement, knee joint capsule closure, hand and wrist collateralligament repair, scapholunate ligament reconstruction, tendon transfersin phalanx, volar plate reconstruction, acetabular labral repair,anterior ligament repair, spinal repair, fracture fixation,cardiovascular surgery, general surgery, gastric surgery, bowel surgery,abdominoplasty, plastic, cosmetic and reconstructive surgery includinglift procedures, forehead lifting, brow lifting, eyelid lifting,facelift, neck lift, breast lift, lateral canthopexy, elevation of thenipple, breast reconstruction, breast reduction, breast augmentation,mastopexy, cystocele and rectocele repair, low anterior resection,urethral suspension, obstetrics and gynecological surgery, NissenFundoplication, myomectomy, hysterectomy, sacrolpopexy, cesareandelivery, general soft tissue approximation and ligation, wound closureincluding closure of deep wounds and the reduction of wide scars andwound hernias, hemostasis, anastomosis, abdominal closure, reinforcementof suture repairs, laparoscopic procedures, partial nephrectomy,vascular grafting, and implantation of cardiac rhythm management (CRM)devices, including pacemakers, defibrillators, generators,neurostimulators, ventricular access devices, infusion pumps, devicesfor delivery of medication and hydration solutions, intrathecal deliverysystems, pain pumps, and other devices to provide drugs or electricalstimulation to a body part.

B. Mesh Products

The discovery that fibers of PBS and copolymers thereof can be preparedwith high initial tensile strengths, and prolonged strength retention,has made it possible to develop mesh implants in particular for use insurgical procedures requiring prolonged strength retention. Notably, thefibers may be prepared with suitable properties for forming surgicalmeshes.

As discussed above, it has been discovered that fibers of PBS andcopolymers thereof can be prepared that do not degrade in the first 4weeks, preferably the first 12 weeks, by surface erosion, which cancause pitting of the surfaces of the fibers. Pitting of fibers isdetrimental to the burst strength of a mesh formed from fibers,particularly when the diameters of the fibers are small. The absence ofpitting makes it possible to produce meshes of PBS and copolymersthereof with more predictable rates of degradation.

It has also been discovered that meshes can be formed from PBS andcopolymers thereof that have improved dimensional stability afterimplantation. As shown in Example 15 and Table 8, meshes comprising PBSand copolymers thereof remain dimensionally stable followingimplantation for at least 4 weeks, and more preferably for at least 12weeks. This is a surprising result in view of comparative data obtainedfor a mesh made from a different material shown in Table 9. The findingis particularly significant when the mesh is used in procedures where itis undesirable for the mesh to shrink and place additional tension onthe mesh. Thus, mesh derived from PBS and copolymers thereof, preferablycomprising monofilament or multifilament oriented fibers, and preferablyknit or woven mesh, is particularly suitable for use in procedures suchas hernia repair, breast reconstruction, mastopexy, tissue lifting,treatment of stress urinary incontinence, pelvic organ prolapse repair,and pelvic floor reconstruction. Porous meshes comprising PBS andcopolymers thereof are particularly suitable for applications where itis desirable to obtain tissue in-growth, such as in hernia repair,breast reconstruction, treatment of stress urinary incontinence withslings, and pelvic floor reconstruction or repair.

It has also been discovered that meshes made from PBS and copolymersthereof do not curl after implantation in vivo. This is anotherimprovement since it prevents curled edges from potentially damagingnearby tissues.

In one embodiment, mesh products may be produced from the high tenacityyarns and high tensile strength monofilaments of poly(butylenesuccinate) and copolymers thereof, for example, by warp or weft knittingprocesses. In a particularly preferred embodiment, the high strengthmonofilament fibers of poly(butylene succinate) and copolymers thereofcan be knitted or woven to make mesh products. In one embodiment,monofilament knitted mesh can be prepared using the following procedure.Forty-nine (49) spools of high strength poly(butylene succinate) orcopolymer thereof monofilament is mounted on a creel, aligned side byside and pulled under uniform tension to the upper surface of a “kiss”roller. The “kiss” roller is spinning while semi-immersed in a bathfilled with a 10% solution of polyethylene glycol sorbitan monolaurate,polyethylene glycol, or other suitable lubricant. The lubricant isdeposited on the surface of the sheet of fiber. Following theapplication of the lubricant, the sheet of fiber is passed into a combguide and then wound on a warp beam. A warp is a large wide cylinderonto which individual fibers are wound in parallel to provide a sheet offibers. Next, warp beams are converted into a finished mesh fabric bymeans of interlocking knit loops. Eight warp beams are mounted inparallel onto tricot machine let-offs and fed into the knitting elementsat a constant rate determined by the ‘runner length’. Each individualmonofilament fiber from each beam is fed through a series of dynamictension elements down into the knitting ‘guides’. Each fiber is passedthrough a single guide, which is fixed to a guide bar. The guide bardirects the fibers around the needles forming the mesh fabric structure.The mesh fabric is then pulled off the needles by the take down rollersat a constant rate of speed determined by the fabric ‘quality’. The meshfabric is then taken up and wound onto a roll ready for scoring. Thepoly(butylene succinate) or copolymer thereof monofilament mesh is thenscoured ultrasonically with water, and may be (i) heat set (for examplein a hot conductive liquid bath or an oven), and then (ii) washed with a70% aqueous ethanol solution.

In an embodiment, the meshes made from monofilaments, multifilaments, orcombinations thereof, of poly(butylene succinate) or copolymers thereofhave one or more of the following properties: (i) a suture pulloutstrength of at least 10 N, or at least 20 N, (ii) a burst strength of0.1 to 100 kgf, more preferably between 1 to 50 kgf, or greater than 0.1kPa, (iii) a thickness of 0.05-5 mm, (iv) an areal density of 5 to 800g/m², (v) pore diameter of 5 μm to 5 mm, or more preferably 100 μm to 1mm, (vi) Taber stiffness of at least 0.01 Taber Stiffness units, morepreferably 0.1-19 Taber Stiffness units, (vii) a degradation rate inphosphate buffered saline at 37° C. wherein the weight average molecularweight of the mesh decreases between 10% and 30% over a 12-week timeperiod, and (viii) a degradation rate in vivo under physiologicalconditions wherein the burst strength of the mesh decreases less than20% at 4 weeks, or wherein the burst strength of the mesh decreases lessthan 35% at 12 weeks. In a preferred embodiment, the monofilament ormultifilament meshes have one or more of the following properties: (i) asuture pullout strength of 1 kgf to 20 kgf, (ii) a burst strength of 1to 50 kgf, more preferably 5 to 30 kgf, (iii) a thickness of 0.1 to 1mm, (iv) areal density of 100 to 300 g/m², and (v) pore diameter 100 μmto 1 mm. In another preferred embodiment, the monofilament ormultifilament mesh of poly(butylene succinate) or copolymer thereof hassubstantially one or more of the following properties: a pore diameterof 500±100 μm, thickness of 0.4±0.3 mm, areal density of approx. 182±50g/m², suture pullout strength of 5.6±2 kgf, and a burst strength of atleast 3 kgf, and more preferably at least 6 kgf.

In one embodiment, the mesh can be combined with an anti-adhesioncoating or film on one surface to make an implant. For example, the meshmay be coated on one side using a hydrogel barrier, such as the Sepra®coating, or using another hyaluronic acid coating. A particularlypreferred mesh comprises oriented monofilament fibers of PBS orcopolymer thereof coated on one side of the mesh with an anti-adhesioncoating or film. Meshes coated with anti-adhesion coatings or films areparticularly useful in hernia repair procedures to prevent adhesions tothe visceral organs.

In another embodiment, the meshes of poly(butylene succinate) orcopolymers thereof may comprise different sized fibers or othernon-poly(butylene succinate) or copolymer thereof fibers, includingmultifilament, and fibers made from other absorbable or non-absorbablebiocompatible polymers and hybrid meshes. Such meshes may be designed sothat their fibers degrade at different rates in vivo.

Meshes comprising poly(butylene succinate) and copolymers thereofprepared as described herein may have a two-dimensional shape, includinga polygon shape, including rectangular, square, triangle, and diamondshapes, a curved shape, including circular, semicircle, elliptical, andcrescent shapes.

In yet another embodiment, the meshes described herein may be used toprepare three-dimensional implants, for example, implants that can beused in breast reconstruction, mastopexy, hernia repair, or in voidfilling. The three-dimensional shapes include cone, dome, partial dome,canoe, hemisphere, plug, and hemi-ellipsoid shapes. In one embodiment,these three-dimensional implants have shape memory that can be used tocontour to the shape of an anatomical structure, or be used to confershape to the patient's tissue. For example, these three-dimensionalimplants can be used in mastopexy and breast reconstruction proceduresto confer shape to the host's breast tissue or form an anatomical shapeof the breast. In one embodiment, these three-dimensional implants haveshape memory that allows them to resume their three-dimension shapeafter delivery into the body (such as laparoscopic delivery), forexample, through a trocar or similar delivery device. Thesethree-dimensional implants can be used for laparoscopic inguinal herniarepair wherein the implant has a three-dimensional shape suitable toconform to the inguinal anatomy, and retain its shape followinglaparoscopic introduction. Suitable three-dimensional implants ofpoly(butylene succinate) and copolymers thereof may be manufactured bymolding a two-dimensional monofilament mesh made from poly(butylenesuccinate) and copolymers thereof. In one process, the mesh may bemolded using a split metal form consisting on an inwardly curving halfand a mating outwardly curving half. The three-dimensional implant maybe formed by draping the mesh over the inwardly curving half of themetal form, placing the outwardly curving half of the metal form otherthe mesh, clamping the split metal form together to form a block, andheating the block to mold the mesh. In another process, thethree-dimensional implants may be plugs, preferably hernia plugs, madefrom meshes of poly(butylene succinate) and copolymers thereof.

In another embodiment, the three-dimensional implants comprisingpoly(butylene succinate) and copolymers thereof maybe implanted in thebreast, preferably instead of breast implants. In a particularlypreferred embodiment, the three-dimensional implants comprise pleats,chambers or compartments. Preferably the pleats, chambers andcompartments are made with monofilament fibers of poly(butylenesuccinate) and copolymers thereof. The chambers or compartments may befilled with tissues during implantation, for example, the chambers orcompartments may be filled with one or more of the following: cells,including stem cells, protein, including collagen, fat and fascia. In aparticularly preferred embodiment, the three-dimensional implants mayhave the shape of a lotus flower or a funnel shape. In an even morepreferred embodiment, the three-dimensional implants may have the shapeof a lotus flower or funnel shape, and are made from monofilament fibersof poly(butylene succinate) or copolymer thereof.

Meshes comprising poly(butylene succinate) or copolymer thereof may alsobe prepared that are expandable. These meshes can be prepared so thatthe fibers of the meshes stretch or elongate so that the meshes canexpand. The meshes may comprise fibers of poly(butylene succinate) orcopolymer thereof that are unoriented, partially oriented or fullyoriented. The meshes may also be designed to expand without the fibersof the meshes stretching. In one embodiment, the meshes may have a knitpattern that provides the mesh with the ability to stretch under force.For example, the mesh may comprise pores that can elongate under force,or loops that can shorten as force is applied. In another embodiment,the meshes may comprise a combination of stronger and weaker fibers,wherein the weaker fibers break when a force is applied allowing themeshes to stretch. Expandable meshes comprising poly(butylene succinate)or copolymer thereof are particularly suitable for use in breastreconstruction, more particularly in combination with the use of atissue expander. The expandable meshes preferably comprise monofilamentfibers made from poly(butylene succinate) and copolymers thereof.

In a further embodiment, the meshes described herein may furthercomprise barbs, hooks, self-anchoring tips, micro-grips, fleece,reinforcement, and a reinforced outer edge or border.

In another embodiment, non-woven meshes may be prepared from the hightenacity yarns by entangling fibers using mechanical methods. Theproperties of the nonwovens can be tailored by selection of parameterssuch as fiber diameter, fiber orientation, and length of the fibers (forstaple nonwovens). In a preferred embodiment, the non-woven meshesprepared from the high tenacity yarns have one or more of the followingproperties (i) a thickness of 0.1-5 mm, (ii) an areal density of 5 to800 g/m², (iii) a suture pullout strength of greater than 10 N, and (iv)a burst strength that is able to withstand a pressure of at least 0.1kPa.

In another embodiment of the invention, the high tenacity yarns ofpoly(butylene succinate) and copolymers thereof, may be knit to producecircular knits. Circular knits comprising the high tenacity yarns may beused, for example, as vascular grafts. In one embodiment, a circularknit of the high tenacity yarns of poly(butylene succinate) andcopolymers thereof may be produced using a single feed, circular weftknitting machine (Lamb Knitting Co., model ST3A/ZA).

In another preferred embodiment of the invention, it has been discoveredthat implantable meshes may also be formed by 3D printing. These meshesare particularly suitable for use in breast reconstruction, herniarepair, pelvic floor reconstruction and treatment of stress urinaryincontinence using slings. Two different methods of 3D printingpoly(butylene succinate) and copolymers thereof are described inExamples 9 and 10. FIG. 1 shows an image of a mesh that was 3D printedaccording to the method of Example 9. The high quality of the mesh isapparent from the image. The method is particularly suitable for formingthree-dimensional mesh implants comprising PBS and copolymers thereof,including, for example, hernia plugs, and meshes with three-dimensionalshapes that are designed to contour to the patient's anatomy. The methodmay also be used to prepare 3D meshes of PBS and copolymers thereof forbreast reconstruction, include breast implants, expandable meshes, andfull contour implants. In an embodiment, the 3D printed mesh implantscomprising PBS or copolymers thereof have one or more of the followingproperties: burst strength of 1 kgf to 25 kgf, and more preferably 3 kgfto 10 kgf; thickness of 50 μm to 3 mm, and more preferably 100 μm to 800μm; pore size between 75 μm and 5 mm; a total porosity of at least 50%,but less than 100%, and a weight average molecular weight of 25 kDa to500 kDa, and more preferably 50 kDa to 300 kDa by GPC relative topolystyrene.

The meshes comprising PBS and copolymers thereof disclosed herein may beused in the following implants: wound closure device, patch, woundhealing device, device for tissue or suture line reinforcement, trachealreconstruction device, organ salvage device, dural patch or substitute,nerve regeneration or repair device, hernia repair device, hernia mesh,hernia plug, inguinal hernia plug, device for temporary wound or tissuesupport, tissue engineering scaffold, guided tissue repair/regenerationdevice, anti-adhesion membrane or barrier, tissue separation membrane,retention membrane, sling, device for pelvic floor reconstruction,urethral suspension device, device for treatment of urinaryincontinence, bladder repair device, void filling device, bone marrowscaffold, ligament repair device or augmentation device, anteriorcruciate ligament repair device, tendon repair device or augmentationdevice, rotator cuff repair device, meniscus repair or regenerationdevice, articular cartilage repair device, osteochondral repair device,spinal fusion device, cardiovascular patch, vascular closure device,intracardiac septal defect repair device, atrial septal defect repairdevice, patent foramen ovale closure device, left atrial appendageclosure device, pericardial patch, vascular graft, myocardialregeneration device, periodontal mesh, guided tissue regenerationmembrane for periodontal tissue, imaging device, anastomosis device,cell seeded device, controlled release device, drug delivery device,plastic surgery device, breast lift device, mastopexy device, breastreconstruction device, breast augmentation device, breast reductiondevice, devices for breast reconstruction following mastectomy with orwithout breast implants, facial reconstructive device, forehead liftdevice, brow lift device, eyelid lift device, face lift device,rhytidectomy device, rhinoplasty device, device for malar augmentation,otoplasty device, neck lift device, mentoplasty device, buttock liftdevice, cosmetic repair device, device for facial scar revision, apouch, holder, cover, enclosure, or casing to partially or fully encase,surround or hold an implantable medical device, a cardiac rhythmmanagement device, a pacemaker, a defibrillator, a generator, animplantable access system, a neurostimulator, a ventricular accessdevice, an infusion pump, a device for delivery of medication andhydration solution, an intrathecal delivery system, a pain pump, ordevice that provides drug(s) or electrical stimulation to the body.

C. Orthopedic Implants

In an embodiment, orthopedic implants may be prepared from polymericcompositions comprising poly(butylene succinate) and copolymers thereof.Optionally, these implants may comprise a ceramic or bioceramic. In oneembodiment, implants may be formed from poly(butylene succinate) andcopolymers thereof, optionally with ceramic present, that includescrews, pins, ACL screws, clips, clamps, nails, medullary cavity nails,bone plates, tacks, fasteners, rivets, staples, fixation devices, bonevoid fillers, suture anchors, bone anchors, osteochondral repairdevices, spinal fusion devices, and device for treatment ofosteoarthritis. It has been discovered that implants can be made fromthe compositions of poly(butylene succinate) and copolymers thereof withhigh stiffness and torsional strength making the implants suitable foruse in orthopedic implants.

In one embodiment, the orthopedic implants may be produced by injectionmolding. For example, injection molded implants of PBS and copolymersthereof may be formed using an Arburg model 221 injection molder usingthe following conditions: barrel temperature of the molder increasingfrom 70° C. at the feed zone to 170° C. at the end of the barrel; andmold temperature of 32° C. After molding, the implants may be dried in avacuum oven at room temperature for 48 hours, and tensile propertiesdetermined using an MTS test machine with a 2 inch/min cross head speed.Representative tensile properties of implants formed by this method areas follows: Young's Modulus 0.66 GPa (96,600 psi), Yield Strength 49.2MPa (7,140 psi) and Break Stress of 71.7 MPa (10,400 psi). Example 8discloses the manufacture of an interference screw by injection molding.The torsional strength of screws made from PBS and copolymer thereof ispreferably between 10 Ncm and 18 Ncm. This strength may be furtherincreased by blending the polymeric compositions with a ceramic prior toinjection molding. A suitable ceramic is tri-calcium phosphate. Suitableblend ratios are 10-50 wt. % of the ceramic. Interference screwsprepared with the bioceramic may have torsional strengths of at least10-20 Ncm, as is disclosed in Example 8.

D. Other Implants

In an embodiment, absorbable stents may be prepared from poly(butylenesuccinate) or copolymers thereof by first producing a tubular stentblank. Tubes may be prepared by melt extrusion, injection molding,solvent dipping, or similar processes that yield a tube with consistentwall thickness of approximately 0.001 to 0.500 mm. The stent structuremay be cut into the blank using mechanical or laser processes to removematerial from selected areas of the tube blank. The stent may bedelivered to a location of the body and deployed by balloon expansion,or removed from a sheath in the body and allowed to self-deploy if thestent is self-expanding. The stent structure provides support to theadjacent tissue and/or delivers therapeutic agents that may be includedin the stent material or coated onto its surface.

In another embodiment, microbeads may be prepared from poly(butylenesuccinate) or copolymers thereof using solvent techniques or meltprocessing approaches. The microbeads may contain a therapeutic agentand may deliver that agent to the tissue after injection into thetissue. The beads may also be used to occlude a blood vessel or provideadditional volume to the tissue.

In a further embodiment, staple line reinforcement material may beprepared from the poly(butylene succinate) or copolymers thereof usingmethods to prepare medical textiles such as knitting, weaving, ornon-woven processes. Alternatively, the staple line reinforcementmaterials may be produced from porous foams of poly(butylene succinate)or copolymers thereof. The staple line reinforcing material may be usedto provide a backing material to weakened or friable tissue that couldnot reliably support a surgical staple or suture. In this way, thestaple line reinforcement material may also function as a pledget orbacking material for a surgical suture. Additionally, the staple linereinforcing material may also be used to seal a tissue and preventleakage of air, blood or other body fluids during a surgical repair.This can facilitate a procedure allowing a surgeon to more quickly,consistently and reliably make a surgical resection, staple linereinforcing material repair, or anastomosis to tissues such as thelungs, blood vessels, bowel or similar tissues.

In another embodiment, absorbable clips for tissue ligation may beprepared from poly(butylene succinate) or copolymers thereof using meltprocessing techniques such as injection molding or 3D printing. Theabsorbable clips may be used when a permanent clip is not desired or totreat a temporary condition. Absorbable clips or cuffs may be useful toprevent or stop bleeding, to restrict flow of material or liquid througha vessel. Bariatric clips or cuffs may be preferred for treating obesityor eating disorders and may be preferred over permanent, invasivesurgeries.

In yet another embodiment, absorbable filters to trap blood clots may beprepared from the poly(butylene succinate) or copolymers thereof. Suchvena cava filters may be preferred over permanent metal or polymerfilters as they could obviate the need for a second procedure to removethe filter after the need for the filter has passed.

V. Methods of Delivering Implants Made from POLY(BUTYLENE SUCCINATE) andCopolymers Thereof

The implants made from poly(butylene succinate) and copolymers thereofmay be implanted using conventional open surgical techniques, but mayalso be implanted using minimally invasive techniques. In oneembodiment, high strength sutures are implanted using arthroscopictechniques. In a particularly preferred embodiment, the high strengthsutures and suture tapes are used for arthroscopic repair of shoulders,elbows, wrists, spine, hips, knees, ankles and feet, including ligamentand tendon repair. In another embodiment, meshes, webs, and latticesmade from high strength monofilaments and high tenacity yarns, or by 3Dprinting of poly(butylene succinate) and copolymers thereof may beimplanted using laparoscopic techniques. In a preferred embodiment,meshes, webs and lattices are implanted for the repair of hernias, andlift procedures, using laparoscopic techniques and other minimallyinvasive techniques.

In a particularly preferred embodiment, the implants may be used in anycurrent mastopexy technique to achieve a breast lift using anyappropriate skin resection pattern. The chosen method will depend uponthe extent of breast ptosis and a number of other factors. The four maintechniques for mastopexy are the: crescent mastopexy, donut (or Benelli)mastopexy, lollipop (or vertical) mastopexy, and anchor (or Weiss orWise) mastopexy. In the crescent mastopexy, a semi-circular incision ismade on the upper side of the areolar, and a crescent shaped piece ofbreast tissue removed. This procedure is typically used for patientswith only mild ptosis where a good lift can be achieved by removingexcess skin on the upper breast, and suturing the skin back in order toelevate the areolar nipple complex. In one embodiment, the implants canbe implanted after further dissection and/or resection to provideadditional support for the upper breast tissue.

The implants can also be implanted during a donut or Benelli mastopexy.In this procedure, a donut shaped piece of breast skin is removed fromaround the areolar with an inner incision line following the perimeterof the areolar, and an outer incision line circling the areolar furtherout. In one embodiment, the implant(s) can be inserted after furtherdissection to support the lift, and a purse string suture used toapproximate the breast skin back to the areolar.

In both the lollipop and anchor mastopexy procedures, incisions are madearound the areolar complex. In the lollipop procedure, a verticalincision is made in the lower breast from the areolar to theinframammary fold, and in the anchor mastopexy procedure an incision ismade across the inframammary fold in addition to the vertical incisionused in the lollipop procedure. The lollipop procedure is generally usedfor patients with moderate ptosis, whereas the anchor procedure isnormally reserved for patients with more severe ptosis. These twoprocedures can be performed with or without breast implant augmentation.In both procedures, breast tissue may be resected, and the resectededges sutured together to create a lift. Prior to suturing the resectedtissue, the implants can be implanted to support the breast, and todecrease the forces on the resected skin and suture line after closure.In a particularly preferred procedure, the implants are positioned tosupport the breast parenchyma or implant, and to minimize the weight ofthe breast on the skin and suture line. In an even more preferredprocedure, the suture line is closed with minimal or no tension on thewound to minimize scar formation.

In a preferred embodiment, when sutured in place, the implants providesupport, elevation and shape to the breast by anchoring of the implantsat one or more locations to the tissue, muscle, fascia or the bones ofthe chest or torso. In a particularly preferred embodiment, the implantsare sutured to the pectoralis fascia or the clavicle. The implants mayalso be sutured to the chest wall or fascia, and in a particularlypreferred embodiment, the implants may be sutured to the chest wall sothat they provide slings for support of the lifted breast or breastimplant.

Modifications and variations of the invention described herein will beobvious to those skilled in the art and are intended to come within thescope of the appended claims.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1: Monofilament Melt Extrusion of Succinicacid-1,4-Butanediol-Malic acid Copolyester with Two Stage Orientation inConvective Chambers to Produce Monofilament Fiber for Implants

Succinic acid-1,4-butanediol-malic acid copolyester (Tepha lot 180333)with weight average molecular weight of 184 kDa, Tm=115° C., (melt flowrate (MFR) at 190° C./2.16 kgf of 5 g/10 min) was dried under vacuumovernight to less than 0.01% (w/w) water. Dried pellets of the polymerwere fed into an extruder barrel of an AJA (Alex James Associates,Greer, S.C.) ¾ single screw extruder (24:1 L:D, 3:1 compression)equipped with a Zenith type metering pump (0.16 cc/rev) and a die with asingle hole spinneret (0.026″, 2:1 L:D) under a blanket of nitrogen. The4 heating zones of the extruder were set at 75° C., 165° C., 180° C. and180° C. The extruder was fitted with a quench bath filled with water at35° C. and set up with an air gap of 10 mm between the bottom of thespinneret and the surface of the water. Two 2-roll godets werepositioned after the quench bath, followed by two sets of longitudinalhot convection chamber/2-roll godet combination. The temperatures of thehot convection chambers were set between 60° to 80° C., followed by2-roll godets then a horizontal winder. Pellets of the copolyester wereallowed to enter the heated extruder barrel, molten polymer passedthrough the barrel, entered a heated block followed by a metering pumpthen a single hole spinneret. The block, metering pump and the spinneretdie were maintained at a constant temperature, preferably 180° C. Pumpdischarge pressure was kept below 1500 psi by controlling thetemperatures and the speed of the metering pump. The resulting spunextrudate filament was free from all melt irregularities. The extrudatewas quenched in a water bath, drawn through longitudinal ovens and woundon a horizontal tension controlled Sahm winder. The results of 3 trialswith in-line orientation and shown in Table 1, together with the resultof a fourth trial where the fiber was not oriented in-line, but ratheroff-line and 10 days after it had been extruded. From inspection ofTable 1, it will be evident that the conditions used to prepare themonofilament fiber resulted in fiber with a tensile strength in therange of 434-518 MPa.

TABLE 1 Properties of monofilament fibers made from PBS copolymerderived from 2-stage orientation in convention ovens Trial #1 #2 #3 #4Orientation Online Online Online Offline Delay None None None 10 daysGodet 1 (m/min) 3.3 3.3 3.3 3.3 Hot Chamber 1 (° C.) 62 62 70 70 Godet 2(m/min) 18.6 18.6 18.5 15 Hot Chamber 2 (° C.) 75 75 80 80 Godet 3(m/min) 22 21 23 22.5 Orientation ratio (total) 6.67 6.36 6.97 6.82Fiber Diameter (mm) 0.178 0.182 0.183 0.172 Tensile Strength (MPa) 452449 434 518 Break Elongation (%) 46 67 41 24

Example 2: Monofilament Melt Extrusion of SuccinicAcid-1,4-Butanediol-Malic Acid Copolyester with Multi Stage IncrementalOrientation in Conductive Chambers to Produce Monofilament Fiber forImplants

Succinic acid-1,4-butanediol-malic acid copolyester (Tepha lot 180333)with weight average molecular weight of 184 kDa, P_(D)=2.83, Tm=115° C.,(MFR 190° C., 2.16 kg, 5 g/10 min) was dried under vacuum overnight toless than 0.01% (w/w) water. Dried pellets of the polymer were fed undera blanket of nitrogen into the extruder barrel of a 2½″ American Kuhnesingle screw extruder (30:1 L:D, 3:1 compression) equipped with a Zenithtype metering pump model HPB917, a die with 0.5 mm-8 hole spinneret and8 heat zones. The 8 heating zones of the extruder were set between 40°C. and 200° C. The extruder was fitted with a quench bath filled withwater at 35°-70° C. and set up with an air gap of 10 mm between thebottom of the spinneret and the surface of the water. Two 5-roll godetswere positioned after the quench bath, followed by three sets of hotconduction chambers fed by godets in order to orient the fiber inmultiple stages. The temperatures of the hot chambers were set upbetween 50° to 90° C. temperature. Another godet was positioned afterthe last chamber, and then a multi-position Sahm winder. The resultsfrom three trials are shown in Table 2. In comparison to the resultsshown in Table 1, the use of multi-stage incremental orientation of thefiber and conductive chambers instead of standard conventionalnon-liquid chambers resulted in monofilament fiber with substantiallyhigher tensile strengths of 779-883 MPa.

TABLE 2 Properties of monofilament fibers made from PBS copolymerderived from multi-stage orientation in conductive liquid chambers Trial#1 #2 #3 Orientation Online Online Online Godet 1&2 (m/min) 3.6 3.6 1Hot Chamber 1 (° C.) 55 55 60 Godet 3 (m/min) 14 14 3.7 Hot Chamber 2 (°C.) 80 80 65 Godet 4 (m/min) 28 28.3 7.7 Hot Chamber 3 (° C.) 85 85 65Godet 5 (m/min) 30 29.7 8.22 Orientation Ratio 8.3 8.25 8.2 Diameter(mm) 0.169 0.166 0.167 Tensile Strength (MPa) 779 752 883 BreakElongation (%) 24 23.7 23 Young's Modulus 2.8 n.d. n.d. (GPa)

Example 3: Multifilament extrusion of Succinic acid-1,4-Butanediol-Malicacid Copolyester to Prepare Implants

Succinic acid-1,4-butanediol-malic acid copolyester (Tepha lot 180333)with weight average molecular weight of 184 kDa, P_(D)=2.83, Tm=115° C.,(melt flow rate (MFR) at 190° C./2.16 kgf of 5 g/10 min), was driedunder vacuum overnight to less than 0.01% (w/w) water. Dried pellets ofthe polymer were fed into an extruder barrel of an AJA (Alex JamesAssociates, Greer, S.C.) ¾″ single screw extruder (24:1 L:D). Theextrusion barrel contained 4 heating zones, a metering pump and a spinpack assembly. The pellets were gravity fed into a chilled feedersection and introduced into the extruder with temperature profile set asfollows: Chimney 40° C.-100° C., Spinneret 170° C.±30° C., Pump 170°C.±30° C., Block 170° C.±30° C., Zone 4 160° C.±40° C., Zone 3 150°C.±40° C., Zone 2 120° C.±50° C., Zone 1 30° C.-40° C., Feed Zone:Ambient temperature. The heated and homogenized melted resin from theextruder was fed into a heated metering pump (melt pump), and from themelt pump the extruded resin was fed into the heated block and thespinneret assembly. The spinneret had 30 holes with a capillary diameterof 0.200 millimeters and a L/D ratio of 2:1. (The spinneret may also beconfigured in other alternative manners. For example, the spinneret canbe configured with capillary diameters from 0.150 to 0.300 millimeters(6 mil to 12 mil) and 15, 120 and 240 holes, as well as higher and lowerdiameters and numbers of holes.) Processing temperature profile rangesfrom 35° C. to 250° C. were used with pressures ranging from 200 to5,000 psi in the barrel and 200 to 5,000 psi in the spin pack. As themolten filaments exited the spin pack they passed through a heatedchimney collar that was 6-12 inches long and ranged in temperature from40° C. to 100° C., and then through an air quench box. The spin pack wassuspended vertically above a yarn take-up roll at a distance sufficientto allow crystallization of the molten filaments and application of spinfinish lubricant. A spin finish solution of 25% polyethylene 25 glycol400 (PEG400) in water was used to hold the filaments together to form ayarn bundle. The speed of the yarn take-up rolls (typically 3-18 metersper minute) was set in proportion to the flow rate of the moltenfilament to control the denier of the as spun yarn bundle. The as spunyarn bundle was then conveyed to a Lessona winder for offline laterorientation or conveyed to a take-up roll for inline orientation on aseries of cold and heated godet pairs and separator rolls. The spinfinish can be reactivated by rewetting the yarn bundle with pure water,and the yarn drawn at ratios from 5 to 14× and temperatures ranging from50° C. to 90° C. The tenacity and denier of the multifilament yarnproduced is shown in Table 3.

TABLE 3 Properties of Multifilament Fibers made from PBS CopolymerPrepared by Melt Extrusion Break Number of Elongation Tenacity FilamentsDenier Load (Kg) (%) (gpd) 15  60 ± 10 0.50 ± 0.05 16% 8.3 30  63 ± 100.79 ± 0.04 20% 12.5 30 152 ± 10 1.55 ± 0.07 21% 10.2 60 309 ± 10 2.80 ±0.10 24% 9.1

Example 4: Preparation of Multifilament Sutures

Oriented yarn produced according to Example 3 and with properties shownin Table 3 was braided using 8 and 16 carrier Steeger braiding equipmentto form the braid constructions shown in Table 4. The mechanicalproperties of the high strength braided sutures, determined according toUSP 24, are also shown in Table 4. The examples include a braid formedas a tape (shown as the last example in Table 4.

TABLE 4 Mechanical Properties of Braids and Tapes Prepared from PBSCopolyester Braid Construction Mechanical Properties Tensile Break LotCore Sheath Pick Diameter strength, elongation Number denier deniercount (mm) (Kg) (%) TE18-008 2 × 152 16 × 152 48 0.608 26.5 39 TE18-0103 × 63  16 × 63  58 0.380 14.2 31 TE18-010 1 × 60  8 × 60 49 0.246 4.326 TE18-021 17 0.5 × 3.0* 62 40 Tape 13 × 6 × Suture 126 denier *Tapedimensions of 0.5 mm thickness and 3.0 mm width

Example 5: Preparation of a Knitted Monofilament Mesh Implants

Monofilament fiber (USP suture size 5/0) prepared according to themethod of Example 2 was processed into knitted mesh according to thefollowing procedure. Monofilament fibers from 49 spools were mounted ona creel, aligned side by side and pulled under uniform tension to theupper surface of a “kiss” 10″ roller. The “kiss” roller was spun whilesemi-immersed in a bath filled with a 10% solution of TWEEN® 20lubricant. The TWEEN® 20 lubricant was deposited on the surface of thesheet of monofilament fibers. Following the application of TWEEN® 20,the sheet of fiber was passed into a comb guide and then wound on a warpbeam. A warp is a large wide cylinder onto which individual fibers arewound in parallel to provide a sheet of fibers. Next, warp beams wereconverted into a finished mesh fabric by means of interlocking knitloops. Eight warp beams were mounted in parallel onto tricot machinelet-offs and fed into the knitting elements at a constant ratedetermined by the ‘runner length’. Each individual monofilament fiberfrom each beam was fed through a series of 20 dynamic tension elementsdown into the knitting ‘guides’. Each fiber was passed through a singleguide, which was fixed to a guide bar. The guide bar directed the fibersaround the needles forming the mesh fabric structure. The mesh fabricwas then pulled off the needles by the take down rollers at a constantrate of speed determined by the fabric ‘quality’. The mesh fabric wasthen taken up and wound onto a roll and scored ultrasonically withwater, heat set in hot water, and then washed with a 70% aqueous ethanolsolution. The knitted mesh produced with monofilament fiber from Example2 had the following properties (as shown in Table 11 at time 0): burststrength of 22.668 kgf, thickness of 0.683 mm, and Taber Stiffness of0.116.

Example 6: Preparation of Knitted Multifilament Mesh Implants

Spools of multifilament fiber prepared according to the method ofExample 3 were processed into knitted multifilament mesh using themethod described in Example 5.

Example 7: Injection Molded Implants

Injection molded implants of succinic acid-1,4-butanediol-malic acidcopolyester (Tepha lot 180333) with weight average molecular weight of184 kDa, Tm=115° C., were prepared using an Arburg model 221 injectionmolder using the following conditions. The barrel temperature of themolder was increased from 70° C. at the feed zone to 170° C. at the endof the barrel. The mold temperature was maintained at 32° C. Aftermolding, the implants were dried in a vacuum oven at room temperaturefor 48 hours, and tensile properties determined using an MTS testmachine with a 2 inch/min cross head speed. Representative tensileproperties of the implants were as follows: Young's Modulus 0.66 GPa(96,600 psi), Yield Strength 49.2 MPa (7,140 psi) and Break Stress of71.7 MPa (10,400 psi).

Example 8: Injection Molded Interference Screws for Use as Implants

Interference screws with a diameter of 7 mm and length of 20 mm wereinjection molded from succinic acid-1,4-butanediol-malic acidcopolyester (Tepha lot 180333), and from the same copolyester afterblending with 50 wt. % beta-TCP (tri-calcium phosphate). The screws wereformed using a similar procedure to that described in Example 7. Afterinjection molding of the screws, the intrinsic viscosity of thecompositions was essentially identical to that of the startingmaterials, indicating little loss of weight average molecular weightduring injection molding occurred. The torsional strength of the screwswas determined by embedding the tip of the molded screws in epoxy resinand measuring the maximum torque achieved by the screwdriver beforefailure of the screws. The average of three screws tested for thecopolyester alone gave a value for torsional strength of 15.0 Ncm. Thetesting was repeated for the screws prepared from the blend, and theaverage value was 18.2 Ncm. For comparison, a commercial ArthrexBiointerference screw for implantation composed of PLLA (poly-L-lacticacid) was also tested. The Arthrex Biointerference screw has an averagefailure torque of 12.1 Ncm.

Example 9: 3D Printed Implantable Mesh

A 3D printed mesh was prepared from succinic acid-1,4-butanediol-malicacid copolyester (Tepha lot 180333), with weight average molecularweight of 184 kDa, Tm=115° C., using melt extrusion deposition accordingto the following method. The mesh was printed using an ARBURGFree-Former machine consisting of a horizontal extruder feeding into avertical ram extruder fitted with motion controlled needle plunger, 200micron spinneret nozzle and a movable stage table. The extruder hopperwas charged with 1½×3 mm sized polymer pellets with a moisture contentof less than 2,000 ppm. The pellets were purged with dry nitrogen in theextruder hopper to maintain dryness. The temperature profile of theextruder was set between 45°-180° C., and the residence time of thepolymer in the extrusion system was maintained at less than 15 min/cm.The conditions resulted in the formation of very high quality printedmesh as shown in FIG. 1.

Example 10: 3D Printed Implantable Lattice

A 3D printed lattice was prepared from succinicacid-1,4-butanediol-malic acid copolyester (Tepha lot 180333), withweight average molecular weight of 184 kDa, Tm=115° C., using selectivelaser melting (SLM). The SLM equipment consisted of a moving powder bedequipped with a reservoir for the polymer granules and a powder sweepergate valve, and a laser source that can direct a laser beam on thepowder bed and focus on a single polymer granule in the bed. Theposition of both the moving powder bed and laser beam were controlled bya computer that had been programmed with 3D CAD data to produce alattice structure of the copolyester. The powder bed could be moved inthe X-Y horizontal plane, and also in the Z axis vertical plane. Thefocal distance, the distance between the lens and surface of the powderwas less than 50 cm. Prior to printing, the polymer was cryo-milledusing liquid nitrogen, and sieved to produce granules with average sizesof 0.3 to 250 μm. The granules were placed in the powder reservoir, anda first layer of powder, 250 μm thick, was spread on the moving bedusing the powder sweeper. The computer driven laser beam was focused oneach polymer granule until it melted, shifting from one granule when itmelted to the next granule. After printing of the first layer, a sweeperarm spread a second layer of polymer granules, the laser position wasadjusted to focus on the granules, and laser firing started to form thesecond 3D layer. The process was repeated with successive layers untilthe lattice made of succinic acid-1,4-butanediol-malic acid copolyesterwas formed.

Example 11: Endotoxin Testing of Copolymer of Succinic Acid and1,4-Butanediol

Polymer pellets of succinic acid-1,4-butanediol-malic acid copolyesterwere tested for endotoxin content using the Bacterial Endotoxin Test(BET) Gel Clot method per USP<85>. Before testing, the pellets weresterilized by exposure to ethylene oxide gas. The extraction wasperformed at a ratio of 1 gram of polymer in 10 mL of endotoxin-freewater; then, a 1:8 dilution of the sample extract was prepared andtested by the gel clot method. The results yielded<2.5 EU/g of polymer.

Example 12: In Vitro Degradation of an Implantable Mesh Prepared fromSuccinic Acid-1,4-Butanediol-Malic Acid Copolyester

The in vitro degradation rate of an implantable mesh prepared fromoriented monofilament fibers of succinic acid-1,4-butanediol-malic acidcopolyester (prepared as described in Example 5) was studied byincubation of the mesh in phosphate buffered saline. The buffer solutioncontained 137 mM NaCl, 2.7 mM KCl, 9.8 mM phosphate and 0.05 wt % sodiumazide and had pH 7.4 at 25° C. The prepared buffer solution was filteredthrough a 0.45 um filter (VWR Product # 10040-470) prior to use. Meshsamples were sterilized by exposure to ethylene oxide gas. Samples (2×2in.) were placed in sterile containers covered in buffer solution andincubated in a shaker incubator at 50 rpm and at a temperature of 37° C.Buffer media was monitored monthly and changed if the pH was outside ofthe targeted value 7.4±0.2. At prescribed time points, the samples wereremoved from the buffer and rinsed with deionized water to remove buffersalts. The samples were then tested for mechanical properties and weightaverage molecular weight retention of the polymer by gel permeationchromatography (as further described in Example 15). The in vitrodegradation data is shown in Table 5.

TABLE 5 Mechanical and Mw data for PBS mesh samples made from orientedPBS monofilament fiber after incubation in phosphate buffered saline (pH7.4) at 37° C. Time Peak Std Strength Mw point Thick Load Dev RetentionMw Std Dev Poly- Retention (weeks) (mm) (kgf) (kgf) (%) (kDa) (Daltons)dispersity (%) 0 0.696 21.773 1.034 100.0 174 0.9 5.26 100.0 2 0.68921.117 1.566 97.0 166 0.2 5.08 95.4 4 0.696 19.923 1.141 91.5 160 0.24.94 92.1 8 0.692 19.537 1.135 89.7 147 0.7 4.58 84.2 12 0.709 18.6301.044 85.6 134 0.8 4.33 77.2

Example 13: In Vitro Degradation of an Implantable Suture Prepared fromSuccinic acid-1,4-Butanediol-Malic acid Copolyester

The degradation rate of an implantable suture prepared from orientedmonofilament fibers of succinic acid-1,4-butanediol-malic acidcopolyester in vitro was studied by incubation of the suture inphosphate buffered saline. The initial properties of the suture areshown in Table 6, line 1 (t=0). The buffer solution contained 137 mMNaCl, 2.7 mM KCl, 9.8 mM phosphate and 0.05 wt % sodium azide and had pH7.4 at 25° C. The prepared buffer solution was filtered through a 0.45um filter (VWR Product # 10040-470) prior to use. Suture samples weresterilized by exposure to ethylene oxide gas. Samples (12 in. length)were placed in sterile containers covered in buffer solution andincubated in a shaker incubator at 50 rpm and at a temperature of 37° C.Buffer media was monitored monthly and changed if the pH was outside ofthe targeted value 7.4±0.2. At prescribed time points, the samples wereremoved from the buffer and rinsed with deionized water to remove buffersalts. The samples were then tested for mechanical properties and weightaverage molecular weight (Mw) retention of the polymer by gel permeationchromatography (as further described in Example 15). The in vitrodegradation data is shown in Table 6.

TABLE 6 Mechanical and Mw data for oriented PBS suture samples afterincubation in phosphate buffered saline (pH 7.4) at 37° C. Time Peak StdBreak Strength Mw point Load Dev Elongation Retention Mw Std Dev Poly-Retention (weeks) (kgf) (kgf) (%) (%) (kDa) (Daltons) dispersity (%) 01.793 0.007 25.133 100.0 174 0.2 4.86 100.0 2 1.801 0.009 25.120 100.4167 0.8 4.93 96.2 4 1.810 0.010 25.364 100.9 163 0.5 4.84 93.6 8 1.7720.020 25.311 98.8 155 1.5 5.78 89.4 12 1.736 0.021 24.866 96.8 146 0.64.85 83.1

Example 14: Elemental Analysis of Succinic Acid-1,4-Butanediol-MalicAcid Copolyester

The elemental composition of the Succinic acid-1,4-Butanediol-Malic acidcopolyester was analyzed by Proton Induced X-ray Emission (PIXE) atElemental Analysis Inc. This method provides quantitative elementalcomposition of a material for inorganic elements sodium through uraniumon the periodic table. The elements found are shown in Table 7. Thepolymer did not contain detectable heavy metals such as Tin, which issometimes used in the manufacture of resorbable polymers such aspoly-glycolide, polylactide and poly-glycolide-co-lactide. The followingtrace elements were detected: silicon 18.98 ppm, titanium 14.77 ppm, andzinc 5.967 ppm.

TABLE 7 PIXE Analysis of a Poly(butylene succinate) Polymer ElementEnergy Det. Limit Concentration Name (keV) 95% Conf. Mass Error Silicon1.740 8.964 ppm 18.980 ppm 5.056 ppm Titanium 4.511 2.362 ppm 14.770 ppm2.057 ppm Zinc 8.639 0.457 ppm  5.967 ppm 0.544 ppm

Example 15: Comparison of In Vivo Properties of an Implantable MeshPrepared from Succinic acid-1,4-Butanediol-Malic acid Copolyester versusan Implantable Mesh Prepared from Poly-4-hydroxybutyrate

The properties of a monofilament knitted mesh prepared from a copolymerof 1,4-butanediol and succinic acid units (the “PBS” mesh), as describedin Example 5, were compared to a commercial mesh, the “GalaFLEX mesh(Galatea Surgical, Lexington, Mass.)” prepared from knitting ofpoly-4-hydroxybutyrate monofilament in an in vivo implantation study inrabbits. The weight average molecular weight of the PBS mesh fibersprior to implantation was 173 kDa. The PBS and GalaFLEX meshes wereimplanted in the dorsal, subcutaneous tissue of New Zealand Whiterabbits to evaluate the local tissue reaction, the degree of tissuein-growth and the changes in mechanical properties of the meshes overtime in vivo. Six (6) female New Zealand White (NZW) rabbits wereimplanted with 6 mechanical (4×4 cm), 1 histological (2×2 cm), and 1scanning electron microscopy (SEM) (2×2 cm) test articles per animal.

Prior to implantation, the rabbits (weighing at least 3.5 kg atimplantation) were anesthetized by an intramuscular injection, followedby maintenance under isoflurane. Following anesthesia, the animals wereinjected subcutaneously with an analgesic. The surgical sites wereprepared for implantation. An incision was made through the skin and theskin was resected laterally by blunt dissection to create a pocket.Three individual mechanical samples (4×4 cm) and 1 histo/SEM sample (2×2cm) were implanted on each side of each animal, for a total of 8specimens per animal. The specimens were implanted by placing the meshflat along the back of the animal without folding or rolling and fixatedwith a Prolene suture at each corner. The skin was closed and a bandagewas applied. The animals were returned to their respective cages,monitored for recovery from the anesthetic, and then monitored daily forgeneral health.

At 4 and 12 weeks, three rabbits were euthanized from each group. Theskin was reflected, the subcutaneous tissues were examined and the areaaround each implant was dissected free. The implanted meshes wererecovered by dissection from the surrounding tissue. The explants wereprocessed for histological, biomechanical and polymer testing. At eachtime point, half of the 4×4 cm implanted meshes (n=9) were tested formechanical properties including the in-grown tissue. The other samples(n=9), were designated for mesh-only analyses and were tested followingcollagenase digestion to remove ingrown tissue and evaluate the residualstrength of the residual polymeric scaffold. In this way, the mechanicalproperties of the mesh alone could be measured and compared to that ofthe combination of mesh and tissue in the composite.

For the mesh-only samples, the in-grown tissue was removed from theexplanted samples using enzymatic digestion with collagenase. Previoustesting demonstrated no impact of the collagenase enzyme on the meshmechanical properties or Mw properties. Individual explanted meshspecimens were placed in a 50 mL Falcon tube containing 25 mLcollagenase (type I) solution (1.0 mg/mL) in TESCA buffer (50 mM TES, 2mM calcium chloride, 10 mM NaN3, pH 7.4, sterile filtered). The tube wasplaced in a shaker (50 rpm) and incubated at 37° C. overnight (˜17 h) todigest and remove tissue attached to the mesh specimen. After theincubation was complete, the specimens were removed from the tubes,residual tissue was manually removed from the explant taking care not todamage the mesh, and the meshes were rinsed with distilled waterfollowed by 70% ethanol. Mesh specimens were blotted dry using alint-free wipe.

Samples were tested for dimensions, relative stiffness (Taber tester),burst strength and evaluated for surface morphology via SEM. Comparisonwas made to non-implanted (T0) articles (n=9/group). Polymer degradationwas further evaluated by Gel Permeation Chromatography (GPC). The hosttissue response and degree of tissue remodeling were evaluatedhistologically

Burst Test, Stiffness & Molecular Weight (Mw) Retention of PBS Mesh

The thickness of each sample was measured with a pro-gage thicknesstester before testing for burst strength. The burst strength wasmeasured using a universal testing machine (Q test Elite by MTS) fittedwith a 1,000 N load cell according to test method ASTM D6797-02,Standard Test Method for Bursting Strength of FabricsConstant-Rate-of-Extension (CRE) Ball Burst Test. The samples wereclamped over the circular opening of the fixture and a ⅜in. probe waslowered through the sample at 305 mm/min until failure. A pre-loadsetting of 0.05 kg was used to remove slack from the sample and registerzero displacement. The load at failure (kgf) was recorded as thebursting strength.

After mechanical testing a portion of the mesh remnant was removed tomeasure the weight average molecular weight (M_(w)) by Gel PermeationChromatography (GPC). Mw was measured relative to monodispersepolystyrene standards using a TOSOH HPLC with Refractive Index detector.Samples for GPC were prepared at 1 mg/ml in chloroform, 100 μl of thesolutions were injected onto a Polymer Labs, PLgel column (5 micron,mixed C, 300=7.5 mm), and eluted at 1 ml/min in chloroform using arefractive index detector. The test results are summarized in Tables 8to 12 below.

Tables 8 and 9 show the dimensions (length, width and area of themeshes) of the PBS mesh and GalaFLEX mesh prior to implantation, andafter implantation for 4 and 12 weeks. The data shows a surprisingdifference between the two meshes. Although both are made with the sameknit patterns and from similar sized monofilament fibers, the dimensionsof the PBS mesh remain essentially constant following implantationwhereas the dimensions of the GalaFLEX mesh change over time. It is thusapparent that the PBS mesh is dimensionally stable followingimplantation, and does not shrink following implantation. The areaoccupied by the mesh remains constant as shown by the relative areaoccupied by the PBS mesh in Table 8, as well as the mesh dimensions.

TABLE 8 Dimensional data for PBS Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue with In-grown Tissue Intact Time LengthSD Width SD Rel Area (weeks) (mm) (mm) (mm) (mm) Area (%) 0 38.0 0.538.4 0.7 1458.8 100.0 4 38.6 0.9 38.9 0.8 1502.6 103.0 12 38.2 0.8 38.41.2 1466.2 100.5

TABLE 9 Dimensional data for GalaFLEX Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue with In-grown Tissue Intact Time LengthSD Width SD Rel Area (weeks) (mm) (mm) (mm) (mm) Area (%) 0 38.1 0.338.1 0.3 1452.5 100.0 4 37.1 1.1 37.4 1.3 1384.4 95.3 12 37.0 1.6 37.02.0 1369.0 94.3

Table 11 shows that the burst strength of the PBS mesh decreases over 12weeks from 22.668 kgf to 16.801 kgf, representing a strength retentionof 74.1%. Table 10 shows that tissue in-growth into the PBS mesh resultsin a lower loss of burst strength when the explant is tested withoutremoval of the in-grown tissue. In this case, the burst strengthdecreases from 22.668 kgf to only 18.288 kgf, representing a strengthretention of 80.7% over the 12-week period. It is apparent from thisdata, that the PBS mesh can support tissue in-growth, and that thisin-growth contributes an additional 80.7%-74.1%=6.6% to the burststrength of the mesh by 12 weeks post-implantation. Table 11 also showsthat the stiffness of the PBS mesh (measured in Taber Stiffness Units)remains relatively constant throughout the 12-week implantation periodeven though the burst strength of the mesh decreases about 25% duringthis period.

TABLE 10 Mechanical Data for PBS Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue with In-grown Tissue Intact Burst BurstStrength Strength Thick. Taber Time Strength SD Retention Thickness SDTaber Stiff. Relative (wks) (kgf) (kgf) (%) (mm) (mm) Stiffness SDStiffness 0 22.668 0.887 100.0 0.683 0.024 0.262 0.116 100.0 4 19.8270.699 87.5 0.716 0.058 0.261 0.094 99.5 12 18.288 0.970 80.7 0.762 0.0720.202 0.083 77.0

TABLE 11 Mechanical data for PBS Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue after Tissue Digestion with Collagenaseto Remove In-grown Fibrotic Tissue Burst Burst Strength Time StrengthStrength Retention Thick. Thick. Taber Taber Rel. (wks) (kgf) SD (kgf)(%) (mm) SD (mm) Stiffness Stiff. SD Stiffness 0 22.668 0.887 100.00.683 0.024 0.262 0.116 100.0 4 19.480 1.831 85.9 0.677 0.027 0.2620.101 100.1 12 16.801 1.086 74.1 0.698 0.008 0.284 0.140 108.4

Table 12 shows the reduction in the weight average molecular weight (Mw)of the PBS polymer used to prepare the PBS mesh implant at 4 and 12weeks compared to the initial Mw. The data demonstrates that the PBSmesh implant degrades in vivo, and that the retention of weight averagemolecular weight of the polymer is 89.7% at 4 weeks, and 72.5% at 12weeks. The finding of the good retention of strength of the PBS meshmeans that it is suitable for use in procedures requiring prolongedstrength retention.

TABLE 12 Weight Average Molecular Weight (Mw) of PBS Mesh Samples afterImplantation Subcutaneously in Rabbit Tissue after Tissue Digestion withCollagenase to Remove In-grown Fibrotic Tissue. Mw Time Mw SD Retention(wks) (kDaltons) (kDaltons) (%) 0 173 0.5 100.0 4 155 0.5 89.7 12 1261.9 72.5

Biocompatibility and Histological of PBS Mesh

At 4 weeks, gross examination showed that the tissue had completelyintegrated into the pores of the mesh implants. Microscopically, markedtissue ingrowth into the implant material was noted at all 3 sites andconsisted of new fibrous connective tissue, neovascularization, andinflammation extending into the spaces between implant material fibers(i.e. the mesh pores).

The tissue reaction of the PBS Mesh was graded relative to thecomparative commercial control, GalaFLEX Mesh. The scores were fairlysimilar between mesh implant types at 4 weeks, with implant materialfibers embedded in a new fibrous connective tissue band, and withmacrophages and multinucleated giant cells being the dominantinflammatory cell types at most sites, surrounding and separating theimplant material fibers. At 4 weeks, there were overall slightly fewermultinucleated giant cells responding to the PBS material fibers than tothe GalaFLEX fibers, and slightly more polymorphonuclear cells. Therewas also slightly less neovascularization overall at the PBS than P4HBsites.

PBS implant sites contained implant material, consisting of roughlycircular, elliptical, or elongate cross-sections through fibers ofclear, refractile, birefringent material arranged in multiple smallclusters in a row parallel to the skin surface (see FIGS. 2 and 3).Implant material fibers had a finely granular texture. Implant materialfibers were surrounded and separated by the peri-implant tissue, whichconsisted of a continuous moderately thick to thick band of mostlyimmature collagen (graded 4), with small foci of mature collagen(graded 1) and with moderate neovascularization. A continuous 1-3cell-thick layer of macrophages (moderate) and multinucleated giantcells (minimal to mild) lined the surface of implant fibers embeddedwithin the fibrous connective tissue band. The new fibrous connectivetissue was infiltrated by variable inflammatory cells, includingscattered to small aggregates of macrophages, multinucleated giantcells, polymorphonuclear cells (minimal to moderate), lymphocytes(minimal), and plasma cells (minimal). Minimal necrosis or apoptosis ofinflammatory cells was an expected finding at sites of inflammation.

Based on the Irritant Rank Score relative to a comparative control mesh(GalaFLEX mesh), the PBS test article was considered a non-irritant. Andthe PBS mesh considered to be biocompatible.

Example 16: Determination of the Strength Retention of a PBS SutureFiber, and its Local Tissue Reaction

PBS oriented monofilament fiber samples (0.109±0.004 mm) (USP suturesize 6/0) were implanted in the dorsal, subcutaneous tissue of NewZealand White rabbits to evaluate the local tissue reaction and thechanges in mechanical properties of the fibers over time in vivo. Three(3) male New Zealand White (NZW) rabbits were implanted with 3mechanical (9 in.), 1 histological/SEM (9 in.) test articles per animal.

Prior to implantation, the rabbits (weighing at least 3.5 kg atimplantation) were anesthetized by an intramuscular injection, followedby maintenance under isoflurane. Following anesthesia, the animals wereinjected subcutaneously with an analgesic. The surgical sites wereprepared for implantation. An incision was made cranially through theskin and a long forcep was tunneled through the subcutaneous tissue andparallel to the spine to exit caudally through a second skin incision. Asingle suture fiber was grasped by the forceps and pulled back into thetissue. This process was repeated to implant each fiber. Four test PBSsuture fibers (3 mechanical samples and 1 histo/SEM sample) and fourcontrol monofilament fibers made of poly-4-hydroxybutyrate (TephaFLEXmonofilament suture, Tepha, Inc. Lexington, Mass.) were implanted oneach side of each animal, for a total of 8 specimens per animal. Theskin was closed and a bandage was applied. The animals were returned totheir respective cages, monitored for recovery from the anesthetic, andthen monitored daily for general health.

At 4 weeks, all three rabbits were euthanized. The skin was reflected,the subcutaneous tissues were examined and the area around each implantwas dissected free. The implanted sutures were recovered by dissectionfrom the surrounding tissue. The explants were processed forhistological, biomechanical and polymer testing. The explanted sutures(n=9) were tested for tensile mechanical properties. The other samples(n=3), were designated for histopathology.

Analysis of the local tissue reaction by histopathology demonstratedthat the PBS suture was graded as a non-irritant relative to thecomparative poly-4-hydroxybutyrate (TephaFLEX) suture control.

Tensile testing was performed on a Universal Testing Machine operatingon the principle of constant rate of elongation of test specimen. Thetensile testing machine was equipped with pneumatic fiber grips, using apre-load setting of 0.05 kg. A gauge length of 138 mm and a strain rateof 300 mm/minute were used. During testing, the location of the breakwas recorded.

After mechanical testing a portion of the suture remnant was removed tomeasure the weight average molecular weight (M_(w)) by Gel PermeationChromatography (GPC). Mw was measured relative to monodispersepolystyrene standards using a TOSOH HPLC with Refractive Index detectoras described above for mesh. The test results are summarized in Table13. The results shown in Table 13 show the PBS monofilament sutureretained 92.7% of its initial weight average molecular weight at 4 weekspost-implantation indicating that the suture had begun to degrade invivo, but could retain substantial strength over a critical woundhealing period.

TABLE 13 Mechanical and Weight Average Molecular Weight (Mw) data forPBS suture samples after subcutaneous implantation in rabbits Time PeakBreak Strength Mw point Load Std Dev Elongation Retention Std DevRetention (weeks) (kgf) (kgf) (%) (%) Mw (kDa) (kDa) (%) 0 1.771 0.03424.063 100 172 1.5 100 4 1.749 0.044 25.694 99 159 0.8 92.7

The subcutaneously implanted oriented PBS monofilament suture fiber wasanalyzed by SEM after it had been implanted for 4 weeks. The SEM imagewas compared to an unimplanted PBS suture fiber. SEM images wererecorded with a 400× magnification. FIG. 4 shows the SEM image of theoriented PBS suture fiber prior to implantation. FIG. 5 shows the SEMimage of the oriented PBS suture fiber after subcutaneous implantationfor 4 weeks. Surprisingly, there is no evidence of surface erosion ofthe implanted PBS suture fiber after 4 weeks in vivo. The SEM image inFIG. 5 shows no evidence of surface erosion of the fiber.

Example 17: Preparation of a Poly(butylene succinate) Mesh Suture

A mesh suture was prepared using triaxial braiding from high strengthmonofilament PBS fibers. Spooled monofilament fibers of succinicacid-1,4-butanediol-malic acid copolyester extruded and oriented asdescribed in Example 2 were unspooled and wound on braider bobbins. Thebobbins were then loaded onto Herzog 4, 8, 16 and 24 carrier braiders.Additional spooled monofilament fiber was used to provide axial fiber inthe mesh suture. The monofilament fibers were unspooled and threadedthrough the hollow axles of the horn gears, and all bobbin and axialfiber ends were pulled through the braiding ring to form the fell point.The braiders' bobbins were allowed to move along the braiding track, andthe braid helix angle was adjusted to 15 degrees at 1 to 2 Picks PerInch (PPI). The constructions (number of carriers and axial fibers usedto prepare the hollow braids) and properties of the triaxial braidedmesh sutures prepared with 100 μm, 150 μm, and 200 μm P4HB monofilamentfiber are shown in Tables 14, 15 and 16. The tables show the outside(OD) and inside (ID) diameters of the mesh suture hollow braids. Thewidth and thickness of the hollow braided mesh sutures were measuredafter the hollow braids had been squashed flat.

TABLE 14 Properties of Triaxial Hollow Braids Prepared with 100 μm PBSMonofilament Fibers Hollow Triaxial Braid Braider Circular FlattenedTensile # # Pillar OD ID Width Thickness Strength Carriers Fibers (mm)(mm) (mm) (mm) (N) 4 2 0.8 0.4 1.2 0.4 47 8 4 1.0 0.6 1.5 0.4 99 12 61.3 0.9 2.0 0.4 149 16 8 1.7 1.2 2.6 0.4 200 24 12 2.8 2.2 3.4 0.4 297

TABLE 15 Properties of Triaxial Hollow Braids Prepared with 169 μm PBSMonofilament Fibers Hollow Triaxial Braid Braider Circular FlattenedTensile # # Pillar OD ID Width Thickness Strength Carriers Fibers (mm)(mm) (mm) (mm) (N) 4 2 1.0 0.4 1.5 0.6 97 8 4 1.5 0.9 2.3 0.6 199 12 62.5 1.9 3.9 0.6 291 16 8 3.0 2.4 4.7 0.6 389 24 12 4.0 3.4 6.2 0.6 584

TABLE 16 Properties of Triaxial Hollow Braids Prepared with 200 μm PBSMonofilament Fibers Hollow Triaxial Braid Braider Circular FlattenedTensile # # Pillar OD ID Width Thickness Strength Carriers Fibers (mm)(mm) (mm) (mm) (N) 4 2 1.1 0.3 1.7 0.8 129 8 4 1.6 0.8 2.5 0.8 259 12 62.5 1.7 3.9 0.8 389 16 8 3.5 2.7 5.4 0.8 518 24 12 5.0 4.1 7.8 0.8 778

Example 18: 3D Printing of a PBS-Malic Acid Copolymer Implant by MeltExtrusion Deposition (MED)

A PBS-malic acid copolymer implant was printed by MED using equipmenthaving a horizontal extruder feeding into a vertical extruder fittedwith a vertical plunger, and a movable stage. The extruder hopper wascharged with PBS-malic acid copolymer pellets (160 kDa, by GPC relativeto polystyrene standards) with a diameter of about 2-3 mm and moisturecontent of about 300 ppm. The pellets were kept dry in the hopper usinga purge of air dried through a silica bed. The temperature profile ofthe horizontal extruder was set to about 30° C. in the build chamber;with the temperatures for the transition zone 1, zone 2; and zone 3(extrusion zone) for various trials as shown in Table 17. The residencetime of the polymer in the MED horizontal extruder was approximately 22min/cm³. The diameter of the nozzle orifice of the vertical extruder was0.2 mm and the drop printing frequency was about 50 drops/sec at theedge of the printed construct and about 240 drops/sec for the in-fill.Under these conditions, it was possible to print implants made fromPBS-malic acid copolymer with good print quality. The weight averagemolecular weight, Mw, of the printed implants was measured by GPC and isalso shown in Table 17. The Mw and polydispersity (PDI) were found tovary with the extrusion conditions used. As is evident from Table 17,the weight average molecular weight of the printed implants increased asthe temperature was raised from 180° C. to 220° C.

We claim:
 1. An implant produced by orienting a polymeric composition,wherein the polymeric composition comprises a 1,4-butanediol unit and asuccinic acid unit, and optionally, wherein the polymeric composition isisotopically enriched.
 2. The implant of claim 1, wherein the implantcomprises an oriented form selected from the group consisting of afiber, mesh, woven, non-woven, film, molded object, patch, tube,laminate or pultruded profile.
 3. The implant of claim 2, wherein thefiber is monofilament, multifilament, braided, or barbed.
 4. The implantof claim 2, wherein the mesh, woven and non-woven forms are knittedmesh, woven mesh, monofilament mesh, or multifilament mesh.
 5. Theimplant of claim 1, wherein the polymeric composition is monoaxially orbiaxially oriented.
 6. An implant comprising a polymeric composition,wherein the polymeric composition comprises a 1,4-butanediol unit and asuccinic acid unit, wherein the implant has a degradation rate, underphysiological conditions, wherein the weight average molecular weight ofthe polymeric composition decreases 3% to 15% over a 4-week time periodin vivo, or wherein the weight average molecular weight of the polymericcomposition decreases 10% to 30% over a 12-week time period in vivo. 7.An implant comprising a polymeric composition, wherein the polymericcomposition comprises a 1,4-butanediol unit and a succinic acid unit,wherein the implant has a degradation rate, and wherein when the implantis incubated at 37° C. in phosphate buffered saline: (i) the weightaverage molecular weight of the polymeric composition decreases between3% and 13% over a 4-week time period, (ii) the weight average molecularweight of the polymeric composition decreases between 5% and 15% over an8-week time period, (iii) the weight average molecular weight of thepolymeric composition decreases between 10% and 30% over a 12-week timeperiod, (iv) the percent mass loss of the implant is between 0% and 5%over a 4-week time period, or (v) the percent mass loss of the implantis between 0% and 5% over an 8-week time period.
 8. An implantcomprising a polymeric composition, wherein the polymeric compositioncomprises a 1,4-butanediol unit and a succinic acid unit, wherein thestrength retention of the implant is greater than 75% at 4 weekspost-implantation, or greater than 65% at 12 weeks post-implantation. 9.The implant of claim 1, wherein the implant is porous.
 10. The implantof claim 6, wherein the polymeric composition has been partially orfully oriented.
 11. The implant of claim 10, wherein the implantscomprise partially or fully oriented monofilament or multifilamentfibers.
 12. The implant of claim 3, wherein the tensile strength of thefibers is between 400 MPa and 1,200 MPa, 500 MPa and 1,200 MPa, 600 MPaand 1,200 MPa, or 700 MPa and 1,200 MPa.
 13. The implant of claim 11,wherein the fibers have a Young's Modulus of at least 600 MPa, 800 MPa,1 GPa, and 2 GPa, but less than 3 GPa.
 14. The implant of claim 11,wherein the fibers have been knit or woven into a mesh.
 15. The implantof claim 2, wherein the mesh has a burst strength between 1 kgf and 100kgf, or between 10 kgf and 30 kgf or a Taber stiffness between 0.01 and10 Taber stiffness units or between 0.1 and 1 Taber stiffness units. 16.The implant of claim 1 wherein: (a) there is no pitting of the surfaceof the implant during degradation in vivo, under physiologicalconditions, for a period of 4 weeks or (b) when implanted underphysiological conditions, in vivo for a period of 4 weeks, thedimensions of the implants do not shrink more than 5% of their initialvalues.
 17. The implant of claim 1, wherein the polymeric compositionfurther comprises (a) one or more of the following: a second diacidunit, a second diol unit, 1,3-propanediol, ethylene glycol,1,5-pentanediol, glutaric acid, adipic acid, terephthalic acid, malonicacid, and oxalic acid; (b) one or more of the following: branchingagent, cross-linking agent, chain extender agent, and reactive blendingagent; or (c) a hydroxycarboxylic acid unit, optionally, wherein thehydroxycarboxylic acid unit has two carboxyl groups and one hydroxylgroup, two hydroxyl groups and one carboxyl group, three carboxyl groupsand one hydroxyl group, or two hydroxyl groups and two carboxyl groups.18. The implant of claim 17, wherein the branching agent, cross-linkingagent, or chain extender unit is selected from one or more of thefollowing: malic acid, maleic acid, fumaric acid, trimethylol propane,trimesic acid, citric acid, glycerol propoxylate, and tartaric acid. 19.The implants of claim 1, wherein the polymeric compositions comprisesuccinic acid-1,4-butanediol-malic acid copolyester, succinicacid-1,4-butanediol-citric acid copolyester, succinicacid-1,4-butanediol-tartaric acid copolyester, succinicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or a combination thereof, succinic acid-adipicacid-1,4-butanediol-malic acid copolyester, succinic acid-adipicacid-1,4-butanediol-citric acid copolyester, succinic acid-adipicacid-1,4-butanediol-tartaric acid copolyester, or succinic acid-adipicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or combinations thereof.
 20. The implant of claim1, wherein the implants further comprise a plasticizer, nucleant,coating, dye, medical marker, bioactive agent, therapeutic agent,diagnostic agent, prophylactic agent, contrast agent, radiopaque marker,radioactive substance, anti-adhesion agent, hyaluronic acid, antibiotic,rifampin, minocycline, collagen, hydroxyapatite, or an absorbablepolymer comprising one or more of the following monomers: glycolic acid,lactic acid, trimethylene carbonate, p-dioxanone, ε-caprolactone,4-hydroxybutyric acid, and 3-hydroxybutyric acid.
 21. The implant ofclaim 1, wherein the polymeric composition: (i) excludes urethane bonds,(ii) is not prepared with a diisocynate, (iii) comprises 1-500 ppm ofone or more, or all, of the following: silicon, titanium, and zinc, (iv)excludes tin or (v) is not a blend of two or more polymers.
 22. Theimplant of claim 1, wherein the polymeric composition has a melttemperature between 100° C. and 150° C., or between 105° C. and 120° C.23. The implants of claim 1, wherein the implant is selected from thegroup: suture, barbed suture monofilament suture, braided suture, meshsuture, wound closure device, patch, wound healing device, wounddressing, burn dressing, ulcer dressing, skin substitute, hemostat,tracheal reconstruction device, organ salvage device, dural patch orsubstitute, nerve regeneration or repair device, hernia repair device,hernia mesh, hernia plug, inguinal hernia plug, device for temporarywound or tissue support, tissue engineering scaffold, guided tissuerepair/regeneration device, anti-adhesion membrane or barrier, tissueseparation membrane, retention membrane, sling, device for pelvic floorreconstruction, device for treatment of pelvic organ prolapse, urethralsuspension device, device for treatment of urinary incontinence, devicefor treatment of stress urinary incontinence, bladder repair device,bulking or filling device, bone marrow scaffold, bone plate, fixationdevice for an implant, ligament repair device or augmentation device,anterior cruciate ligament repair device, tendon repair device oraugmentation device, rotator cuff repair device, meniscus repair orregeneration device, articular cartilage repair device, osteochondralrepair device, spinal fusion device, cardiovascular patch, catheterballoon, vascular closure device, intracardiac septal defect repairdevice, including but not limited to atrial septal defect repair devicesand PFO (patent foramen ovale) closure devices, left atrial appendage(LAA) closure device, pericardial patch, vein valve, heart valve,vascular graft, myocardial regeneration device, periodontal mesh, guidedtissue regeneration membrane for periodontal tissue, ocular cellimplant, imaging device, cochlear implant, anastomosis device, cellseeded device, cell encapsulation device, controlled release device,drug delivery device, plastic surgery device, breast lift device,mastopexy device, breast reconstruction device, breast augmentationdevice, breast reduction device, breast implant, devices for removal,reshaping and reorienting breast tissue, devices for breastreconstruction following mastectomy with or without breast implants,facial reconstructive device, forehead lift device, brow lift device,eyelid lift device, face lift device, rhytidectomy device, thread liftdevice, device to lift and support sagging areas of the face, brow andneck, rhinoplasty device, device for malar augmentation, otoplastydevice, neck lift device, mentoplasty device, buttock lift device,cosmetic repair device, and device for facial scar revision.
 24. Theimplant of claim 23, wherein the implant is a braided suture comprisingan oriented multifilament fiber, wherein the breaking strength of thebraided suture is from 40 N to 270 N, and optionally, wherein the suturehas an in vivo strength retention, under physiological conditions, at4-6 months, of at least 40%.
 25. The implant of claim 1, wherein theimplant contains less than 20 endotoxin units per implant as determinedby the limulus amebocyte lysate (LAL) assay.
 26. A method for making theimplant of claim 1, wherein the polymeric composition comprises a1,4-butanediol unit and a succinic acid unit, comprising: providing thepolymeric composition and forming or incorporating the polymericcomposition into an implant by one or more processes comprising:casting, solvent casting, solution spinning, solution bonding of fibers,melt processing, extrusion, melt extrusion, melt spinning, fiberspinning, orientation, relaxation, annealing, injection molding,compression molding, lamination, dry spinning, knitting, weaving,crocheting, melt-blowing, film formation, film blowing, film casting,membrane forming, electrospinning, thermoforming, pultrusion,centrifugal spinning, molding, tube extrusion, spunbonding, nonwovenfabrication, entangling of staple fibers, fiber knitting, weaving andcrocheting, mesh fabrication, coating, dip coating, laser cutting,barbing, punching, piercing, pore forming, lyophilization, stitching,calendering, freeze-drying, phase separation, particle leaching, thermalphase separation, leaching, latex processing, gas plasma treatment,emulsion processing, 3D printing, fused filament fabrication, fusedpellet deposition, melt extrusion deposition, selective laser melting,printing of slurries and solutions using a coagulation bath, or printingusing a binding solution and granules of powder.
 27. The method of claim26, wherein the implant is selected from the group consisting of suture,barbed suture, wound closure device, patch, wound healing device, wounddressing, burn dressing, ulcer dressing, skin substitute, hemostat,tracheal reconstruction device, organ salvage device, dural patch orsubstitute, nerve regeneration or repair device, hernia repair device,hernia mesh, hernia plug, inguinal hernia plug, device for temporarywound or tissue support, tissue engineering scaffold, guided tissuerepair/regeneration device, anti-adhesion membrane or barrier, tissueseparation membrane, retention membrane, sling, device for pelvic floorreconstruction, device for treatment of pelvic organ prolapse, urethralsuspension device, device for treatment of urinary incontinence, devicefor treatment of stress urinary incontinence, bladder repair device,bulking or filling device, bone marrow scaffold, bone plate, fixationdevice for an implant, ligament repair device or augmentation device,anterior cruciate ligament repair device, tendon repair device oraugmentation device, rotator cuff repair device, meniscus repair orregeneration device, articular cartilage repair device, osteochondralrepair device, spinal fusion device, cardiovascular patch, catheterballoon, vascular closure device, intracardiac septal defect repairdevice, including but not limited to atrial septal defect repair devicesand PFO (patent foramen ovale) closure devices, left atrial appendage(LAA) closure device, pericardial patch, vein valve, heart valve,vascular graft, myocardial regeneration device, periodontal mesh, guidedtissue regeneration membrane for periodontal tissue, ocular cellimplant, imaging device, cochlear implant, anastomosis device, cellseeded device, cell encapsulation device, controlled release device,drug delivery device, plastic surgery device, breast lift device,mastopexy device, breast reconstruction device, breast augmentationdevice, breast reduction device, breast implant, devices for removal,reshaping and reorienting breast tissue, devices for breastreconstruction following mastectomy with or without breast implants,facial reconstructive device, forehead lift device, brow lift device,eyelid lift device, face lift device, rhytidectomy device, thread liftdevice, device to lift and support sagging areas of the face, brow andneck, rhinoplasty device, device for malar augmentation, otoplastydevice, neck lift device, mentoplasty device, buttock lift device,cosmetic repair device, and device for facial scar revision.
 28. Amethod of enhancing the healing of a wound, injury, or defect in a siteof a patient, or repairing or regenerating tissue in a site of apatient, comprising administering at the site an implant comprising apolymeric composition, wherein the polymeric composition comprises a1,4-butanediol unit and a succinic acid unit, wherein the implant has:(a) an oriented form of the polymeric composition, (b) a degradationrate, under physiological conditions, wherein the weight averagemolecular weight of the polymeric composition decreases 3% to 15% over a4-week time period, or wherein the weight average molecular weight ofthe polymeric composition decreases 20% to 35% over a 12-week timeperiod, (c) a degradation rate, wherein when the implant is incubated at37° C. in phosphate buffered saline: (i) the weight average molecularweight of the polymeric composition decreases between 3% and 13% over a4-week time period, (ii) the weight average molecular weight of thepolymeric composition decreases between 5% and 15% over an 8-week timeperiod, (iii) the percent mass loss of the implant is between 0% and 5%over a 4-week time period, or (iv) the percent mass loss of the implantis between 0% and 5% over an 8-week time period, or (d) a strengthretention that is greater than 75% at 4 weeks post-implantation, or astrength retention that is greater than 65% at 12 weekspost-implantation.